Epidermodysplasia verruciformis (EV) is a rare disease caused by human papillomavirus (HPV) infection. Part of skin lesions at the exposed site would become malignant, but few cases with squamous cell carcinoma (SCC) transformation at unexposed sites have been reported. In December 2016, one EV patient with squamous cell carcinoma transformation at unexposed sites (perianal region) were admitted and treated at our hospital. Here we reported the clinicopathological characteristics and our surgical management of the SCC skin lesion of this EV patient. We deem that once local malignant transformation occurs, early surgical resection should be performed, and skin without lesions at the unexposed sites should be selected as the donor site for skin graft or skin flap transplantation.