Progression of human melanoma is associated with changes in antigenic phenotypes of tumor cells. To establish whether inflammatory infiltrates in progressing melanoma also change, we studied 146 cutaneous melanomas at different stages of progression. Monoclonal antibodies (MAbs) against lymphocyte and macrophage subpopulations, interleukin-2 receptor (IL-2 R), immune interferon (IFN-gamma), and the IFN-gamma-inducible, progression-associated melanoma antigens HLA-DR and gp89 were applied in situ. During the course of melanoma progression, decreased amounts of peritumoral T cells, IL-2 R-expressing lymphocytes and dermal T6+ dendritic cells were found, while increased numbers of intratumoral T cells, inflammatory (27E10+) and mature (25F9+) macrophages were associated with local progression of primary melanomas. In metastases, most infiltrate components except 25F9+ macrophages were rare. Positive correlations were observed between: (1) dermal T6+ cells and IL-2 R+ lymphocytes, and (2) presence of IFN-gamma in the infiltrate and HLA-DR and gp89 antigens on tumor cells. In all stages, HLA-DR expression on tumor cells was correlated with: (1) a shift towards T8+ lymphocytes in the infiltrates and (2) a loss of IL-2 R expression. Our data suggest mutual influences between melanoma cells and mononuclear cell infiltrates in situ.