We show that murine interferons (IFNs)-alpha/beta and -gamma induce expression of the protooncogene c-fos in F9 embryonal carcinoma cells, NIH-3T3 cells, and other tissue culture cells. The induction of c-fos mRNA is rapid and transient in that the mRNA appears within 15 min and disappears by 2 h following IFN treatment. The protein synthesis inhibitor cycloheximide (CHX) also stimulates rapid but more stable expression of c-fos mRNA in these cells. Treatment of these cells with a combination of CHX and IFNs results in superinduction of c-fos mRNA. In contrast, IFNs do not affect c-myc mRNA expression in these cells. These results suggest that c-fos gene expression plays a role in signal transduction following binding of IFNs to the receptors.