Experimental hepatic necrosis was induced in phenobarbital pretreated rats by means of the intraperitoneal administration of an acetaminophen-dimethyl sulfixide (DMSO) mixture. Cytochrome P-450 content and the specific activities of aminopyrine demethylase, aniline hydroxylase and bilirubin glucuronyl transferase diminished over the three-day study period, as compared with control animals. The reductions, however, were generally modest; not uniform for all the enzymes assayed; and correlated poorly with histologic necrosis and standard liver function tests. It is concluded that in acute liver disease changes in the hepatic in vitro drug metabolizing enzyme capacity may not be closely related to cellular necrosis, per se, and the degree of change in enzyme activities will vary from one enzyme system to another. These findings may explain, in part, the often inconsistent alterations in the disposition and elimination of drugs described in associated liver disease.