This study assessed effects of exposure to p-xylene, a ubiquitous air pollutant, on mice infected with murine cytomegalovirus (MCMV), a mouse model for a common human virus. It was postulated that adverse health effects could occur as a result of (1) enhanced infection due to xylene-induced immune suppression, (2) increased p-xylene toxicity due to viral suppression of cytochrome P-450 (P-450), and/or (3) additive or synergistic effects on liver function due to tissue injury by both p-xylene and MCMV. Mice were exposed to filtered air, 600 or 1200 ppm p-xylene 6 h/d for 4 d and infected with a sublethal dose of MCMV after the first exposure. No deaths occurred among uninfected, p-xylene-exposed mice or infected, air-exposed mice; 34% and 0% mortality occurred respectively in infected mice exposed to 1200 and 600 ppm p-xylene. Virus titers in the liver and splenic natural killer cell activity were unaffected by exposure to 1200 ppm p-xylene. Small but significant increases in serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase activities, indicators of liver damage, were observed at 4 d postinfection. p-Xylene exposure had no effect on these serum enzyme activities in uninfected mice, but 1200 ppm potentiated this effect in infected mice. MCMV significantly suppressed and p-xylene significantly increased total P-450 levels in the liver, but there was no significant interaction between the two. Isozymes 1A1, 2B1/B2, and 2E1 were decreased to a similar degree, suggesting that the virus does not target specific isozymes. Enhanced mortality was not due to immune suppression. While p-xylene potentiated liver damage was caused by the virus, the magnitude of serum enzyme activities indicates that this damage was not a likely cause of death. The cause of deaths is unclear, results were consistent with the hypothesis that enhanced mortality was related to enhanced xylene toxicity due to suppression of P-450, although additive or synergistic damage to tissues other than liver cannot be ruled out.