Langerhans cells function as potent antigen-presenting cells in the epidermis. They were shown to play an essential role in the mechanisms of defense of the skin against viral infections. In the present study, the response of Langerhans cells to infection of the skin with vaccinia virus was investigated. Decrease in Langerhans cell density in the skin was accompanied by an increase in the pathogenicity of the WR and Noguchi but not of the Lister strain of vaccinia virus. Langerhans cell density was shown to increase rapidly at the site of inoculation with the two pathogenic strains of vaccinia virus.