HSV-2 induces the transcription of c-fos gene in both human (diploid) cell strains and mouse (heteroploid) cell lines. HSV-1 is incapable of such induction. The induction of transcription is rapid and transient in both cell types. The product of transcriptional induction of c-fos in mouse cells is mainly a 4.5 kb fos mRNA along with lesser amount of a 2.2 kb fos mRNA, while in human cells the 4.5 kb mRNA is the only detectable product. Both the 4.5 kb and 2.2 kb fos mRNAs are mature gene products as judged by their presence exclusively in the cytoplasm of infected mouse L929 cells, while a 3.5 kb putative precursor of the 2.2 kb fos mRNA appears exclusively in the nucleus. In infected human WI38 cells, the 4.5 kb mRNA also appears exclusively in the cytoplasm. Virus specific protein synthesis is an absolute requirement for the transcriptional activation. The 4.5 kb fos mRNA is under different control mechanisms since it is not induced by serum stimulation of serum starved cells as is the 2.2 kb fos transcript. Moreover, in serum starved cells simultaneously stimulated by serum and infected, only the 2.2 kb fos transcript can be superinduced by the protein synthesis inhibitor cycloheximide, while the appearance of the 4.5 kb fos mRNA is completely blocked by this treatment.