diff --git a/gufe/protocols/errors.py b/gufe/protocols/errors.py
index b9256e46..3dddf9d6 100644
--- a/gufe/protocols/errors.py
+++ b/gufe/protocols/errors.py
@@ -26,3 +26,11 @@ class MissingUnitResultError(ProtocolDAGResultError):
 
 class ProtocolUnitFailureError(ProtocolDAGResultError):
     """Error when a ProtocolDAGResult has only ProtocolUnitFailure(s) for a given ProtocolUnit."""
+
+
+class ExecutionInterrupt(BaseException):
+    """Exception for unrecoverable execution failures that are unrelated to user inputs.
+
+    Will not be caught by ``ProtocolUnit.execute()``.
+
+    """
diff --git a/gufe/protocols/protocolunit.py b/gufe/protocols/protocolunit.py
index fba47adb..56dcd750 100644
--- a/gufe/protocols/protocolunit.py
+++ b/gufe/protocols/protocolunit.py
@@ -21,6 +21,7 @@
 from typing import Any, Dict, List, Optional, Tuple, Union
 
 from ..tokenization import TOKENIZABLE_REGISTRY, GufeKey, GufeTokenizable
+from .errors import ExecutionInterrupt
 
 
 @dataclass
@@ -327,9 +328,8 @@ def execute(
                 start_time=start,
                 end_time=datetime.datetime.now(),
             )
-
-        except KeyboardInterrupt:
-            # if we "fail" due to a KeyboardInterrupt, we always want to raise
+        except (KeyboardInterrupt, ExecutionInterrupt):
+            # NOTE: this statement is for clarity, these Interrupts will raise regardless.
             raise
         except Exception as e:
             if raise_error:
diff --git a/gufe/tests/test_protocolunit.py b/gufe/tests/test_protocolunit.py
index 51a37a47..c3f153fe 100644
--- a/gufe/tests/test_protocolunit.py
+++ b/gufe/tests/test_protocolunit.py
@@ -3,6 +3,7 @@
 
 import pytest
 
+from gufe.protocols.errors import ExecutionInterrupt
 from gufe.protocols.protocolunit import Context, ProtocolUnit, ProtocolUnitFailure, ProtocolUnitResult
 from gufe.tests.test_tokenization import GufeTokenizableTestsMixin
 
@@ -27,6 +28,16 @@ def _execute(ctx: Context, an_input=2, **inputs):
         return {"foo": "bar"}
 
 
+class DummyExecutionInterruptUnit(ProtocolUnit):
+    @staticmethod
+    def _execute(ctx: Context, an_input=2, **inputs):
+
+        if an_input != 2:
+            raise ExecutionInterrupt
+
+        return {"foo": "bar"}
+
+
 @pytest.fixture
 def dummy_unit():
     return DummyUnit(name="qux")
@@ -77,6 +88,26 @@ def test_execute(self, tmpdir):
             with pytest.raises(ValueError, match="should always be 2"):
                 unit.execute(context=ctx, raise_error=True, an_input=3)
 
+    def test_execute_ExecutionInterrupt(self, tmpdir):
+        with tmpdir.as_cwd():
+
+            unit = DummyExecutionInterruptUnit()
+
+            shared = Path("shared") / str(unit.key)
+            shared.mkdir(parents=True)
+
+            scratch = Path("scratch") / str(unit.key)
+            scratch.mkdir(parents=True)
+
+            ctx = Context(shared=shared, scratch=scratch)
+
+            with pytest.raises(ExecutionInterrupt):
+                unit.execute(context=ctx, an_input=3)
+
+            u: ProtocolUnitResult = unit.execute(context=ctx, an_input=2)
+
+            assert u.outputs == {"foo": "bar"}
+
     def test_execute_KeyboardInterrupt(self, tmpdir):
         with tmpdir.as_cwd():
 
diff --git a/news/add_execution_interrupt.rst b/news/add_execution_interrupt.rst
new file mode 100644
index 00000000..b3826fd5
--- /dev/null
+++ b/news/add_execution_interrupt.rst
@@ -0,0 +1,23 @@
+**Added:**
+
+* Added ExecutionInterrupt, a special exception that does not get handled as a ``ProtocolUnitFailure``.
+
+**Changed:**
+
+* <news item>
+
+**Deprecated:**
+
+* <news item>
+
+**Removed:**
+
+* <news item>
+
+**Fixed:**
+
+* <news item>
+
+**Security:**
+
+* <news item>