diff --git a/api/python/quilt3/packages.py b/api/python/quilt3/packages.py
index 5bb913520d5..a9f5394b70d 100644
--- a/api/python/quilt3/packages.py
+++ b/api/python/quilt3/packages.py
@@ -34,6 +34,7 @@
     legacy_calculate_checksum,
     legacy_calculate_checksum_bytes,
     list_object_versions,
+    list_objects,
     list_url,
     put_bytes,
 )
@@ -841,7 +842,7 @@ def _load(cls, readable_file):
             gc.enable()
         return pkg
 
-    def set_dir(self, lkey, path=None, meta=None, update_policy="incoming"):
+    def set_dir(self, lkey, path=None, meta=None, update_policy="incoming", unversioned: bool = False):
         """
         Adds all files from `path` to the package.
 
@@ -858,6 +859,7 @@ def set_dir(self, lkey, path=None, meta=None, update_policy="incoming"):
                 If 'incoming', whenever logical keys match, always take the new entry from set_dir.
                 If 'existing', whenever logical keys match, retain existing entries
                 and ignore new entries from set_dir.
+            unversioned(bool): when True, do not retrieve VersionId for S3 physical keys.
 
         Returns:
             self
@@ -910,10 +912,13 @@ def set_dir(self, lkey, path=None, meta=None, update_policy="incoming"):
             src_path = src.path
             if src.basename() != '':
                 src_path += '/'
-            objects, _ = list_object_versions(src.bucket, src_path)
+            if not unversioned:
+                objects, _ = list_object_versions(src.bucket, src_path)
+                objects = filter(lambda obj: obj["IsLatest"], objects)
+            else:
+                objects = list_objects(src.bucket, src_path, recursive=True)
+
             for obj in objects:
-                if not obj['IsLatest']:
-                    continue
                 # Skip S3 pseduo directory files and Keys that end in /
                 if obj['Key'].endswith('/'):
                     if obj['Size'] != 0:
@@ -1134,7 +1139,15 @@ def manifest(self):
         for logical_key, entry in self.walk():
             yield {'logical_key': logical_key, **entry.as_dict()}
 
-    def set(self, logical_key, entry=None, meta=None, serialization_location=None, serialization_format_opts=None):
+    def set(
+        self,
+        logical_key,
+        entry=None,
+        meta=None,
+        serialization_location=None,
+        serialization_format_opts=None,
+        unversioned: bool = False,
+    ):
         """
         Returns self with the object at logical_key set to entry.
 
@@ -1154,6 +1167,7 @@ def set(self, logical_key, entry=None, meta=None, serialization_location=None, s
                 https://github.com/quiltdata/quilt/blob/master/api/python/quilt3/formats.py
             serialization_location(string): Optional. If passed in, only used if entry is an object. Where the
                 serialized object should be written, e.g. "./mydataframe.parquet"
+            unversioned(bool): when True, do not retrieve VersionId for S3 physical keys.
 
         Returns:
             self
@@ -1162,9 +1176,18 @@ def set(self, logical_key, entry=None, meta=None, serialization_location=None, s
                          entry=entry,
                          meta=meta,
                          serialization_location=serialization_location,
-                         serialization_format_opts=serialization_format_opts)
+                         serialization_format_opts=serialization_format_opts,
+                         unversioned=unversioned)
 
-    def _set(self, logical_key, entry=None, meta=None, serialization_location=None, serialization_format_opts=None):
+    def _set(
+        self,
+        logical_key,
+        entry=None,
+        meta=None,
+        serialization_location=None,
+        serialization_format_opts=None,
+        unversioned: bool = False,
+    ):
         if not logical_key or logical_key.endswith('/'):
             raise QuiltException(
                 f"Invalid logical key {logical_key!r}. "
@@ -1181,7 +1204,7 @@ def _set(self, logical_key, entry=None, meta=None, serialization_location=None,
             size, version_id = get_size_and_version(src)
 
             # Determine if a new version needs to be appended.
-            if not src.is_local() and src.version_id is None and version_id is not None:
+            if not src.is_local() and src.version_id is None and version_id is not None and not unversioned:
                 src.version_id = version_id
             entry = PackageEntry(src, size, None, None)
         elif isinstance(entry, PackageEntry):
diff --git a/api/python/tests/integration/test_packages.py b/api/python/tests/integration/test_packages.py
index b00926df154..84bcb1fd1a2 100644
--- a/api/python/tests/integration/test_packages.py
+++ b/api/python/tests/integration/test_packages.py
@@ -631,6 +631,25 @@ def test_set_dir_wrong_update_policy(self):
             pkg.set_dir("nested", DATA_DIR, update_policy='invalid_policy')
         assert expected_err in str(e.value)
 
+    @mock.patch("quilt3.packages.list_objects")
+    @mock.patch("quilt3.packages.list_object_versions")
+    def test_set_dir_unversioned(self, list_object_versions_mock, list_objects_mock):
+        list_objects_mock.return_value = [
+            {
+                "Key": "foo/bar.txt",
+                "Size": 123,
+            },
+        ]
+
+        pkg = Package().set_dir(".", "s3://bucket/foo", unversioned=True)
+
+        list_object_versions_mock.assert_not_called()
+        list_objects_mock.assert_called_once_with("bucket", "foo/", recursive=True)
+        assert [
+            (lk, e.get())
+            for lk, e in pkg.walk()
+        ] == [("bar.txt", "s3://bucket/foo/bar.txt")]
+
     def test_package_entry_meta(self):
         pkg = (
             Package()
@@ -746,6 +765,17 @@ def test_set_package_entry_as_object(self):
             file_path = pkg[lk].physical_key.path
             assert not pathlib.Path(file_path).exists(), "These temp files should have been deleted during push()"
 
+    @patch("quilt3.packages.get_size_and_version", mock.Mock(return_value=(123, "v1")))
+    def test_set_package_entry_unversioned_flag(self):
+        for flag_value, version_id in {
+            True: None,
+            False: "v1",
+        }.items():
+            with self.subTest(flag_value=flag_value, version_id=version_id):
+                pkg = Package()
+                pkg.set("bar", "s3://bucket/bar", unversioned=flag_value)
+                assert pkg["bar"].physical_key == PhysicalKey("bucket", "bar", version_id)
+
     def test_tophash_changes(self):
         test_file = Path('test.txt')
         test_file.write_text('asdf', 'utf-8')
diff --git a/docs/CHANGELOG.md b/docs/CHANGELOG.md
index 83cce4182cf..94b275be1dc 100644
--- a/docs/CHANGELOG.md
+++ b/docs/CHANGELOG.md
@@ -17,6 +17,7 @@ Entries inside each section should be ordered by type:
 
 # unreleased - YYYY-MM-DD
 ## Python API
+* [Added] New 'unversioned' parameter to `Package.set_dir()` and `Package.set()` for use with S3 URIs, such as HealthOmics, that do not support `ListBucketVersions` and/or `GetObjectVersion` ([#3927](https://github.com/quiltdata/quilt/pull/3927))
 * [Removed] Drop Python 3.7 support ([#3841](https://github.com/quiltdata/quilt/pull/3841))
 * [Changed] Set S3 client `max_pool_connections` to `QUILT_TRANSFER_MAX_CONCURRENCY` ([#3867](https://github.com/quiltdata/quilt/pull/3867))
 * [Changed] **BREAKING:** Switch from a regular SHA256 checksum to a hash list (`sha2-256-chunked`) to match S3's built-in checksums ([#2782](https://github.com/quiltdata/quilt/pull/2782))
diff --git a/docs/api-reference/Package.md b/docs/api-reference/Package.md
index c9c87ce4907..f3b023e165d 100644
--- a/docs/api-reference/Package.md
+++ b/docs/api-reference/Package.md
@@ -131,7 +131,7 @@ json decode error
 invalid package exception
 
 
-## Package.set\_dir(self, lkey, path=None, meta=None, update\_policy='incoming')  {#Package.set\_dir}
+## Package.set\_dir(self, lkey, path=None, meta=None, update\_policy='incoming', unversioned: bool = False)  {#Package.set\_dir}
 
 Adds all files from `path` to the package.
 
@@ -149,6 +149,7 @@ __Arguments__
     If 'incoming', whenever logical keys match, always take the new entry from set_dir.
     If 'existing', whenever logical keys match, retain existing entries
     and ignore new entries from set_dir.
+* __unversioned(bool)__:  when True, do not retrieve VersionId for S3 physical keys.
 
 __Returns__
 
@@ -230,7 +231,7 @@ fail to create file
 fail to finish write
 
 
-## Package.set(self, logical\_key, entry=None, meta=None, serialization\_location=None, serialization\_format\_opts=None)  {#Package.set}
+## Package.set(self, logical\_key, entry=None, meta=None, serialization\_location=None, serialization\_format\_opts=None, unversioned: bool = False)  {#Package.set}
 
 Returns self with the object at logical_key set to entry.
 
@@ -251,6 +252,7 @@ __Arguments__
 * __https__: //github.com/quiltdata/quilt/blob/master/api/python/quilt3/formats.py
 * __serialization_location(string)__:  Optional. If passed in, only used if entry is an object. Where the
     serialized object should be written, e.g. "./mydataframe.parquet"
+* __unversioned(bool)__:  when True, do not retrieve VersionId for S3 physical keys.
 
 __Returns__