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In patients with Epidermolysis Bullosa (EB), surgery may be required to remove Squamous Cell Carcinoma (SCC) of the hands or to correct pseudo-syndactyly. Dermal substitutes may represent a suitable tool to promote the healing of surgical wounds in EB. We review our experience with a collagen-elastin dermal matrix to promote surgical wound healing due to hand surgery to correct pseudo-syndactyly or SCC resection in patients affected by EB. Overall, 12 patients (mean age, 29±11 years, range 13-51; four females) with EB were considered, with a total of 25 different interventions (16 SCC removals; three amputations for recurrent infiltrating SCC; six pseudo-syndactyly corrections). All patients received a collagen-elastin dermal matrix sheet. Neodermis was achieved in all patients, and no adverse events potentially associated with the graft occurred. No SCC recurrence was reported at sites operated for either SCC resection or amputation. The opening of the first or second commissure appears to be maintained for over 1 year after the procedure, preserving digital function. We believe that the application of a dermal substitute, together with a close dressing protocol, may represent a suitable strategy for obtaining physiological tissue regeneration and maintaining proper hand function in patients with EB.