Background: Effective and tolerable therapeutic strategies for patients with refractory persistent epithelial defects (PEDs) are limited and generally provide poor outcomes. This retrospective case review describes four refractory cases of PEDs associated with recurrent corneal erosions (RCEs) and dry eye disease (DED), which were successfully treated with cyclosporine eye drops. Methods: Patients were treated with cyclosporine A 0.05% eye drops twice a day for at least 12 months. At enrolling time, each patient was asked to suspend topical steroids or other eye drops used for ocular surface abnormalities with the exception of lubricants and eye washing. A complete evaluation of ocular surface symptoms was performed including the McMonnies Dry Eye Questionnaire, Ocular Surface Disease Index, slit-lamp biomicroscopy, fluorescein break-up time, the fluorescein staining of the cornea and conjunctiva (according to the Oxford grading system), the Schirmer I test, and the meibomian secretion after digital pressure application on the lids. This set of exams was carried out at baseline and repeated at all follow-up assessments. Results: All participants that did not benefit from previous therapies, including corticosteroids tapering schedule, showed an important improvement in the clinical picture after two months with topical cyclosporine medication. Moreover, after 12 months of continuous therapy, all patients showed a clinical improvement in DED signs and symptoms, related to the absence of new RCE episodes. The treatment was well tolerated, and no adverse effects were reported. Conclusion: Although a small number of cases were available of our analysis, the treatment with cyclosporine eye drops represents a promising approach in the management of refractory PEDs with associated ocular comorbidities, since it may reduce the RCE episodes and improve the tear film stability, in absence of systemic or local side effects.