Two human malignant melanoma cell lines, Malme-3M and SK-Mel-28, were analyzed for their ability to induce the expression of intercellular adhesion molecule 1 (ICAM-1) and human leukocyte antigen (HLA)-DR molecules on their cell surfaces as well as at the transcriptional level before and after treatment with interferon (IFN)-γ. Both cell lines demonstrated a high percentage(> 99% ) of ICAM-1 expression regardless of IFN-γ treatment. Before IFN-γ treatment, Malme-3M cells barely expressed HLA-DR molecules (< 2% ) and SK-Mel-28 cells demonstrated a relatively high percentage(> 50% ) of HLA-DR expression. Both cell lines displayed elevated levels of HLA-DR expression in a time dependent manner after IFN-γ treatment. However, these two cell lines have been shown to respond differentially to IFN-γ. The molecular mechanism underlying such a differential behavior was investigated, and HLA-DR gene regulation was studied at the transcriptional level. Treatment with IFN-γ led to the steady-state mRNA augmentation of the HLR-DR gene. The HLA-DRA mRNA augmentation was similar in both cell lines, whereas in Malme-3M, IFN-γ did not augment the rate of transcription of the HLA-DRB gene as much as in SK-Mel-28. Data from this study established the fact that the melanoma cell lines displayed a differential susceptibility to IFN-γ on the modulation of HLA-DR molecules, and this modulation was transcriptionally regulated.