Three human melanoma cell lines of varying invasive and metastatic potential were analyzed for their ability to express HLA-DR antigens on the cell surface as well as transcriptionally at the mRNA level in the presence and absence of IFN-gamma treatment. Cells of low and intermediate metastatic and invasive potential showed a high percentage of HLA-DR surface expression, both before (91.2-99.9%) and after (97.8-99.9%) IFN-gamma treatment, as quantitated by flow cytometry. In contrast, cells of high metastatic and invasive potential expressed barely detectable levels of HLA-DR-positive cells before IFN-gamma treatment (0.3-0.6%) and displayed elevated levels following treatment (42.3-89.4%). Allowing the highly metastatic cells to recover for 7 or 14 days following IFN-gamma treatment resulted in barely detectable levels of HLA-DR-positive cells. Northern blot analyses of HLA-DR transcription levels showed a strong expression in cells of low and intermediate metastatic and invasive potential. HLA-DR mRNA levels were not detectable in control cells of high metastatic potential nor in those cells which had undergone 7- and 14-day recovery periods following IFN-gamma treatment. There was, however, an induction of HLA-DR expression in the cells that had been treated with IFN-gamma for 72 hr and allowed no recovery period. In addition, a punctate, receptor-like pattern of immunofluorescence staining pattern for cell surface HLA-DR was seen after a 72 hr IFN-gamma treatment in the highly metastatic cells. In contrast, cells of low and intermediate metastatic potential expressed a homogeneous ring-like pattern of antigen expression.