21 years of follow-up study of a family with epidermodysplasia verruciformis (e.v.) have shown that members of one family can be infected with different human papillomaviruses (HPVs), either HPV 3 or HPV 4, and sometimes with both. The clinical picture resembled disseminated flat warts in cases induced by HPV 3, whereas in those caused by HPV 4 there were flat red or red-brownish plaques and depigmented pityriasis versicolor-like lesions. Malignancies developed only in family members infected with HPV 4, whereas the cases due to HPV 3 ran a more benign and slowly progressive or stationary course. There were also abortive and regressive cases, and the 3 children in whom the wart-like lesions did not recur after removal had an unimpaired cell-mediated immunity (CMI). In all cases of e.v., irrespective of the inducing virus, CMI was low, which seems to be an important factor in the pathogenesis of the disease. Humoral antibodies directed specifically against HPV 3 were present in the majority of the cases, mainly those infected with HPV 3.