The effect of a single oral dose of 2‐butanol (2.2 ml/kg) or 2‐butanone (1.87 ml/kg) on hepatic ultrastructure and drug‐metabolizing enzyme activity was studied in the rat. A 135–197% increase in acetanilide hydroxylase activity was found in rats sacrificed 12–40 h after dosing with 2‐butanol or 2‐butanone. A 40‐h pretreatment with 2‐butanone produced a 155% increase in aminopyrine N‐demethylase activity. NADPH‐cytochrome c reductase activity and the concentrations of cytochromes P‐450 and b5were largely unaltered 2–40 h after dosing with either agent. Electron microscopic examination of hepatocytes from rats sacrificed 76 h after 2‐butanol or 2‐butanone revealed a marginal increase in the prevalence of smooth endoplasmic reticulum. However, by 40 h, there was a marked proliferation of the smooth endoplasmic reticulum and reduction in rough endoplasmic reticulum in response to both agents. The most marked potentiation of CCI4hepatotoxicity occurred when rats were pretreated with 2‐butanol or 2‐butanone 76 h before CCI4administration. The coincidental finding of maximal CCI4‐induced hepatic injury and elevation of microsomal xenobiotic activity within the same time frame following 2‐butanol or 2‐butanone supports the hypothesis that aliphatic alcohols and ketones potentiate CCI4hepatotoxicity by enhancing biotransformation of the halocarbon to cytotoxic metabolites.