Cocaine is a potent hepatotoxin in mice. It is converted in the liver by a minor oxidative pathway to the active metabolite, norcocaine nitroxide. Previous studies have shown evidence of a lipid peroxidative mechanism of toxicity, including increased conjugated diene absorption by hepatic microsomal lipids following a single 60 mg per kg i.p. dose of cocaine in DBA/2Ha mice. To explore this mechanism further, morphologic changes in the livers of DBA/2Ha mice were examined following the same dose of cocaine. The first ultrastructural change seen was dilatation of rough endoplasmic reticulum in centrilobular hepatocytes 1 hr following cocaine injection, coincident with the previously observed onset of increased conjugated diene absorption in microsomal lipids. During the previously observed period of peak conjugated diene absorption (2 to 4 hr), ultrastructural changes in centrilobular hepatocytes progressed. These included focal mitochondrial membrane disruption followed by more extensive mitochondrial swelling and disruption with increased swelling of rough endoplasmic reticulum. Changes in size, shape and concentration of histochemically labeled, morphometrically studied peroxisomes were also seen during this interval. Injury of centrilobular hepatocytes advanced to cell death in 6 to 8 hr. The time course and nature of these morphologic findings correlate with previously observed evidence of lipid peroxidation, supporting the hypothesis that this is the mechanism of cocaine hepatoxicity.