Nine different human melanomas and 16 clones, isolated from 2 of them, were characterized for susceptibility to rIL1-beta-, rIL4-, rTNF-alpha- and rIFN-gamma-mediated effects on proliferation and surface expression of class-II HLA (DR and DP), ICAM-1 and LFA-3 molecules and of 3 tumor-associated antigens (recognized by MAb 763.74T, 149.53 and R24). In spite of marked inter- and intra-tumor heterogeneity for susceptibility to the effects of each cytokine, the most frequent upregulation was induced on the HLA class-II antigens by rIFN-gamma and on adhesion molecules by rIFN-gamma, rTNF-alpha and rIL1-beta, while tumor-associated antigens were often down-modulated by rIFN-gamma. Tumor heterogeneity was also evident on tumor-cell proliferation with an apparent hierarchy in the frequency and extent of inhibitory effects: rIFN-gamma greater than rTNF-alpha greater than rIL1-beta = rIL4. Combinations of 2 cytokines resulted in rare and limited changes in the antigenic profile in comparison to the effects seen with single factors, while the combination of rTNF-alpha and rIFN-gamma resulted in significant synergistic antiproliferative effects on most tumor cells and clones. Taken together, these results indicate that single cytokines can profoundly affect the antigenic profile of melanoma cells, while strong tumor-growth inhibition is often achieved by combinations of 2 cytokines acting in synergism.