Hepatotoxicity of diethyldithiocarbamate (DDC) was investigated in rats. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were markedly elevated 24 hr after subcutaneous administration of DDC and histologically, the liver showed submassive necrosis. A sustained inhibition in the liver of Cu,Zn-superoxide dismutase (Cu-SOD) activity was observed following DDC treatment. DDC produced a significant loss in liver reduced glutathione (GSH) level after 1 hr, but the nadir was observed later than that of Cu-SOD. Catalase activity decreased gradually from 7 hr. Thiobarbituric acid reactive substances (TBARS) in the liver were significantly increased from 15 hr. Hepatic haemodynamics were scarcely changed up to 15 hr. Desferrioxamine (a chelator of iron) and piperonyl butoxide (an inhibitor of cytochrome P-450) prevented DDC-induced increases of both ALT and TBARS, but GSH did not, DDC hepatotoxicity was not changed by phenobarbital induction. Thus, we have shown that subcutaneous dose of DDC caused hepatotoxicity in rats. Although the exact sequence of its hepatotoxic factors is unproven, it seems likely that lipid peroxidation through the dysfunction of antioxidant defence factors and a toxic metabolite contribute to the formation of this liver injury.