Natural cell-mediated cytotoxicity of peripheral blood mononuclear cells was studied in eight patients with epidermodysplasia verruciformis induced by human papillomaviruses specific for epidermodysplasia verruciformis and in five patients with epidermodysplasia verruciformis-induced exclusively by human papillomavirus type 3. Nine patients with various cutaneous warts and 25 age- and sex-matched healthy persons were control subjects. Natural cell-mediated cytotoxicity against both K-562 erythroleukemic and Sk-v cells was in the normal range in patients with epidermodysplasia verruciformis induced by epidermodysplasia verruciformis-specific human papillomaviruses and in patients with cutaneous warts. The lysis of both targets, however, was significantly decreased in patients with the form of epidermodysplasia verruciformis associated with human papillomavirus type 3. Experiments with normal keratinocytes and with keratinocytes isolated from a malignant lesion bearing human papillomavirus type 5 genomes showed that the latter were susceptible to lysis by the peripheral blood mononuclear cells of healthy persons and of patients with cutaneous warts. Lysis of keratinocytes in epidermodysplasia verruciformis, however, was strongly reduced in patients with epidermodysplasia verruciformis induced by specific human papillomaviruses. This reduction was not associated with a decrease in anti-K-562 natural cell-mediated cytotoxicity. Our results suggest that in patients with epidermodysplasia verruciformis induced by disease-specific human papillomaviruses, there is reduced natural cell-mediated cytotoxicity against epidermodysplasia verruciformis keratinocytes.