Plasma glutathione is markedly decreased in human cirrhosis of the liver. This decrease is said to be caused by reduced concentrations of liver glutathione. However, several studies on hepatic glutathione have revealed its concentrations to be unchanged, decreased, or even elevated. To test these inconsistencies we investigated the glutathione status of plasma, liver, and kidney in rats chronically exposed to carbon tetrachloride (CCl4). After 14 weeks of CCl4 treatment, histological examination revealed progressive cirrhotic transformation. After 20 weeks, complete micro-nodular cirrhosis was present and distinct ascites had developed. Plasma reduced glutathione (GSH) decreased by 34% in the early and by 44% in the late group, paralleled by a 65% and 76% decrease of plasma oxidized glutathione (GSSG). Liver GSH in early stages of cirrhosis was reduced by 49%, but in late cirrhosis it did not differ from controls. In contrast, liver GSSG increased by 35% in the early and by 191% in the late group. Kidney GSH increased by 14% in early and 44% in late stage cirrhosis. Kidney GSSG was unchanged in the early group, but increased by 18% in the late group. The decrease of plasma GSH and GSSG is closely related to the severity of experimental cirrhosis and inversely related to an increase of hepatic oxidized glutathione. The hepatic content of reduced glutathione, however, is decreased in early cirrhosis only. According to these results the inconsistent findings in man could be due to differences in the stages of cirrhosis in the patients. The increase in kidney glutathione is a new finding that needs further investigation, but it may probably be related to kidney dysfunction in liver disease.