This study has shown for the first time an association between the metastatic properties of two autologous melanoma cell lines and their susceptibility to induction of HLA class II Ag by IFN-gamma. After in vitro incubation with IFN-gamma the melanoma cell line MeWo did not acquire reactivity with anti-HLA class II antibodies, whereas its metastatic variant MeM 50-10 did. The differential susceptibility to induction of HLA class II Ag on the two cell lines cannot be accounted for by either differences in the number and affinity of IFN-gamma receptors or in the sensitivity to IFN-gamma, but most likely reflects an intrinsic property of each cell line. Serologic and immunochemical investigations with anti HLA-DR, DQ, and DP mAb have indicated that only HLA-DR Ag are induced by IFN-gamma on MeM 50-10 cells. Northern blot analysis with HLA-DR beta, DQ beta, and DP beta probes suggest that different mechanisms underlie the differential susceptibility to induction by IFN-gamma of the gene products of the HLA-D region. The regulatory mechanism(s) that control the expression of HLA class II Ag appear to be different from those controlling the expression of the melanoma-associated Ag tested, inasmuch as the modulation of the latter by IFN-gamma did not differ on the two melanoma cell lines.