Provided are novel methods and systems for inspecting photomasks to identify lithographically significant contamination defects. Inspection may be performed without a separate reference image provided from a database or another die. Inspection techniques described herein involve capturing one or more test images of a photomask and constructing corresponding test “simulation” images using specific lithographic and/or resist models. These test simulation images simulate printable and/or resist patterns of the inspected photomask. Furthermore, the initial test images are used in parallel operations to generate “synthetic” images. These images represent a defect-free photomask pattern. The synthetic images are then used for generating reference simulation images, which are similar to the test simulation images but are free from lithographically significant contamination defects. Finally, the reference simulation images are compared to the test simulation images to identify the lithographically significant contamination defects on the photomask.