Primary human epidermal cell cultures composed of keratinocytes and melanocytes were exposed to supernatants of phytohaemagglutinin (PHA)-stimulated T cells, various lymphokines and interferon-beta, and checked for the emergence of HLA-DR antigen using immunofluorescence and immunoelectron microscopy. HLA-DR expression was induced by the supernatants and human recombinant interferon-gamma (rIFN-gamma), whereas recombinant interferon-alpha 2, interleukin-2 and non-recombinant human interferon-beta had no such effect. The threshold concentration of rIFN-gamma required to induce this phenomenon was 10 IU/ml; no further increase of reaction intensity was observed using doses of more than 100 IU/ml. Maximum reaction intensity was achieved after 72 h of incubation; a minimum of 3 h of incubation with rIFN-gamma followed by 72 h incubation in rIFN-gamma-free medium proved sufficient to induce HLA-DR expression. The inductive effect of the supernatants and rIFN-gamma could be completely abrogated by pretreatment with excess doses of the monoclonal antibody GZ4 specific for human IFN-gamma. Keratinocytes and melanocytes reacted in an identical fashion both qualitatively and quantitatively in all experiments. These data indicate that IFN-gamma possesses specific signal functions in the induction of HLA-DR expression on epidermal cells.