Epidermodysplasia verruciformis (EV) is considered as a model of genetic cancer due to unusual susceptibility to EV-specific human papillomaviruses (HPVs). We established an in vivo experimental system for long-term propagation of EV tissue which should facilitate the study of tumor progression in EV. Skin fragments from benign and early pre-malignant lesions of 6 EV patients were grafted under the kidney capsule of athymic mice. After several months the grafted tissue formed epidermal cysts. These cysts showed typical EV cytopathic effect, in situ hybridization revealed the presence of HPV 5, 8, 9, 12 and 36 DNA, and immunoperoxidase staining detected papillomavirus-group-specific antigens in the permissive cells of the cysts. In some cysts, there were numerous mitoses and downward proliferation of the epidermis with slight dyskeratotic changes. The experimental system described constitutes a model for studies on the role of HPV and other co-factors in human cutaneous carcinogenesis.