Aberrant immune responses may play a role in the susceptibility of patients with epidermodysplasia verruciformis to human papilloma virus (HPV). We examined the stimulatory capacity of antigen-presenting cells from HPV-infected skin and peripheral blood T-cell responses of patients with epidermodysplasia verruciformis. The percentage of Langerhans cells in relation to total epidermal cells in suspension was slightly reduced in HPV-infected lesions, relative to apparently clinically uninfected epidermis. In addition, the morphologic appearance of Langerhans cells was altered in lesional epidermal sheets. Despite these abnormalities, Langerhans cells were functionally intact in their capacity to present alloantigens to T cells and, in fact, the epidermis of HPV-infected lesions demonstrated enhanced antigen-presenting activity in three of four patients tested. The antigen-presenting activity was entirely abrogated by removal of Langerhans cells and was not associated with increased activity of cytokines with stimulatory activity for the thymocyte co-stimulation assay. Although epidermodysplasia verruciformis T cells were unresponsive to autologous HPV-infected epidermis, they responded well to mitogens, allogeneic mononuclear leukocytes, and allogeneic epidermal cells. Epidermodysplasia verruciformis T cells were inhibited in their capacity to respond to allogeneic epidermal cells when they were simultaneously exposed to autologous epidermal cells from HPV-infected lesional epidermis, but not to normal-appearing epidermis. Thus, although Langerhans cell activity is intact in epidermodysplasia verruciformis, these individuals fail to respond to autologous papillomas, which may, at least in part, be explained by an interaction between papillomal epidermal cells and autologous T cells that results in an inhibited response.