Susceptibility to murine cytomegalovirus (MCMV) was enhanced by treating B6C3F1 and CD-1 mice subcutaneously with 10 mg 7,12-dimethylbenz(a)anthracene (DMBA)/kg fractionated over a 2 week period. One week after the final DMBA treatment mice were infected with a sublethal dose of MCMV. Virus-augmented natural killer cell (NKC) activity was depressed in B6C3F1 mice treated with DMBA while serum interferon (IFN) levels were unaffected. Susceptibility to MCMV was not affected by treating mice with 400 mg benzo(a)pyrene (B(a)P)/kg using the same exposure regimen. Virus-augmented NKC activity was suppressed in B(a)P treated mice, but the magnitude of the suppression (18%) was much less than that observed for DMBA-treated mice (56%). Susceptibility to MCMV, virus-augmented NKC, and IFN induction were not affected in mice treated intraperitoneally with 50 mg cyclosporin A (CSA)/kg/day for 5 days and infected with a sublethal dose of MCMV on the 5th day of treatment. The data suggest that chemicals which depress NKC are likely to enhance susceptibility to MCMV, and conversely that effects on NKC should be suspected when chemical exposure enhances susceptibility to MCMV.