Background: Hereditary epidermolysis bullosa (EB) is a rare genodermatosis characterized by skin fragility and blistering of the skin and mucous membranes in reaction to minimal traumas. The development of cutaneous squamous cell carcinomas (cSCCs) is one of the most common medical complications in junctional and dystrophic forms of the disease. Complete surgical excision of cutaneous tumors represents the gold standard of treatment. However, not only recognition of cSCCs can be challenging in the affected skin but also wound closure after surgical excision poses a great therapeutic challenge in EB patients. The aim of our study was to analyze the postoperative outcomes of such patients in order to have a better knowledge of the main critical issues in their surgical management and oncological follow-up., Methods: We retrospectively identified a cohort of five EB patients treated at Modena University Hospital. Collected data included patient age and sex, date of cSCC diagnosis, relapses/recurrences, site of the neoplasm, number of surgical interventions, use of dermal substitutes, and postoperative infections., Results: A total of 26 cSCCs were detected in our cohort. Forty-one surgical interventions were necessary to achieve excision of cSCCs with clear margins, varying from 1 to 4 surgical sessions per cSCC. Dermal substitutes were used in most cases but carried a higher infectious risk., Conclusions: EB patients tend to develop numerous cSCCs that often relapse even after complete excision with clear margins. These results stress the importance of early cSCC diagnosis and strict postsurgical follow-up., (© 2022 The Authors. International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)