Clinical trials with interferon (INF) treatment in patients with advanced metastatic melanoma have met with limited success, suggesting that only a small subgroup of patients with melanoma is sensitive to INF therapy. For therapeutic strategies, it would be of great value to discriminate and define markers related to the anti-proliferative effects of INF. In the present study, we report on the in vitro growth inhibitory effects of INF in six human melanoma cell lines; this is associated with a modulation of cell surface markers. The responsiveness of human melanoma cell lines in vitro to INF-alpha shows a good correlation with a specific immunophenotype (TA99-/EGF-R+ or HLA-DR+). No marker correlated with sensitivity or resistance to INF-beta or INF-gamma. This is the first report identifying cell surface markers of human melanoma cells which might have a predictive value for the clinical response to INF-alpha.