In this study, we evaluated the effect of ras oncogene activation on cell response to interferons (IFNs). For this purpose, we treated NIH 3T3 murine fibroblasts transformed by transfection with K-, Ha-, or N-ras oncogenes, either mutated or amplified, for 24 hours with IFN-gamma or IFN-alpha. We evaluated cell response by measuring virus replication, [3H]thymidine incorporation, 2',5'-oligoadenylate synthetase activation, and class I antigen induction. Transformed cells were much less responsive to IFN-gamma antiviral and antiproliferative activities than normal NIH 3T3 cells. Similarly, the induction of 2',5'-oligoadenylate synthetase following IFN-gamma treatment was completely depressed in transformed cells. Only class I antigens, measured at the cell surface and mRNA levels, appeared partially inducible by IFN-gamma in ras-transformed cells. When the same cell lines were treated with IFN-alpha, we observed full response. Because both normal and ras-transformed NIH 3T3 cells were able to bind [125I]IFN-gamma with comparable Kd values (8.3 X 10(-11) M vs. 3 X 10(-11) M, respectively), these findings suggest that ras oncogenes may differentially impair IFN-gamma activities by affecting activation of IFN-inducible genes downstream from the receptor binding event.