We studied the effects of various immunologic and inflammatory mediators on the expression of the class II major histocompatibility antigens, HLA-DR and DQ in short-term organ cultures of newborn human foreskin. Induction of these molecules above baseline was observed preponderantly on microvascular endothelium and epidermal dendritic cells, and among the mediators tested, this induction was caused exclusively by immune interferon. Increased reactivity for HLA-DR and DQ was observed at 24 hours for both cell types. Double labeling confirmed that the HLA-DR/DQ-positive dendritic cell population consisted largely of T6-positive Langerhans cells. Peak endothelial HLA-DR expression was seen at 24 hours and slowly dissipated thereafter. In contrast, endothelial HLA-DQ showed increasing expression over 72 hours of the study. Keratinocytes remained unreactive for HLA-DR and DQ during the entire study period. We conclude that class II major histocompatibility molecules can be modulated on skin microvascular endothelial cells and Langerhans cells in situ by immune interferon with response rates different from those previously described for endothelium in cell culture. Furthermore, the organ culture system has revealed keratinocyte unresponsiveness not anticipated from cell culture experiments. These findings have implications for the effector function and potential targeting of these cells in the cutaneous immune response, and establishes short-term organ culture of human skin as a valuable model for assessment of interactions between cytokines and skin cells.