Although systemic and local autoimmune diseases are the primary possibilities in the differential diagnosis of noninfectious peripheral ulcerative keratitis (PUK), other unusual etiologies such as systemic or local malignancies also must be considered. We report on two patients with PUK whose study led to the discovery and subsequent treatment of a chronic myelogenous leukemia and a sebaceous cell carcinoma of the eyelid, respectively. The results emphasize the need for meticulous diagnostic pursuit, including the possibility of malignancy in patients with peripheral ulcerative keratitis.