We examined the effect of cigarette smoke in rats on antipyrine (AP) disposition in blood and AP metabolites in urine and compared these results with those after pretreatment with tar, 3-methylcholanthrene (3-MC), and phenobarbital (PB) in the same species. In vitro hepatic monooxygenase activities were also examined in smoke-exposed and tar-pretreated rats and compared to saline-pretreated or control rats. Both the smoke-exposed and tar-pretreated rats showed a significant (p less than 0.05) increase in AP clearance as compared to the control rats. The increases in AP clearance of PB and 3-MC groups were more remarkable (p less than 0.01), being more than three and eight-fold greater than the control group, respectively. The urinary amount of 4-hydroxyantipyrine (4OHA) was significantly (p less than 0.05) greater and that of norantipyrine (NORA) and AP less (p less than 0.05) in the smoke-exposed rats than in the controls. This trend was not observed in the tar-pretreated rats. In the 3-MC-treated rats a significant (p less than 0.05) increase in the urinary amount of 4OHA was found, while that of 3HMA was significantly (p less than 0.01) diminished without a change in AP or NORA in the urine. In the PB-pretreated rats the trend was similar to the 3-MC group except that the amount of unchanged AP was significantly (p less than 0.05) decreased. In the study of in vitro hepatic monooxygenase activities 7-ethoxycoumarin O-deethylase was significantly (p less than 0.01) increased in the smoke-exposed rats but not in the tar-treated rats. There was no significant increase in the content of cytochrome P-450 or aminopyrine N-demethylase in the two groups examined in the study. These results suggest that the metabolic pathways of AP, a multimetabolized drug, would be affected differently with different experimental inducers and that smoke and tar act somewhat differently on the hepatic monooxygenase system resulting in the different profiles of AP metabolites in rat urine.