The effect of human leukocyte Interferon (IFN) on the in vitro growth and expression of melanoma-associated antigens (MAA), β₂-microglobulin (β₂m) and HLA-DR antigen on cultured human melanoma cells was studied. Exposure of melanoma cells to IFN for 64 hours resulted in a dose-dependent inhibition of growth with 46% reduction in cell number at 10³ U IFN/ml and 74% reduction at 10⁵ U/ml. Quantitative absorption experiments in the mixed hemadsorption assay determined that the expression of MAA and β₂m on treated cells was enhanced at 10²–10⁵ U IFN/ml, twofold to fivefold for MAA and fivefold to twelvefold for β₂m. No change was seen in HLA-DR antigen expression. The IFN-induced enhancement of MAA and β²m could be detected as early as after 16 hours and a maximum expression was reached at 96 hours after IFN exposure. The IFN-induced enhancement of MAA and β₂m on melanoma cells was reversible. Studies with melanoma cells grown in stationary phase and serum-deprived conditions indicated that IFN-induced augmentation of MAA and β₂m did not require cell proliferation. The data suggest that the effect of IFN on antigen expression is independent of its effect on cell growth. Further studies are needed to fully elucidate the mechanism.