Apoptosis is one of the events that are involved in liver fibrogenesis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. We have recently reported that Salvia miltiorrhiza plays a protective role in carbon tetrachloride (CCl4)-induced hepatic fibrosis. In this study, we aimed to evaluate whether S. miltiorrhiza modulated CCl4-induced hepatic apoptosis in rats. Male Wistar rats were given orally either vehicle or water-extract of S. miltiorrhiza (50 mg kg(-1) twice daily) for nine weeks beginning from the start of CCl4 administration. A group of normal rats was included for comparison. Hepatocyte DNA fragmentation and cytosolic caspase-3 and caspase-8 activity were determined in the experimental animals. Hepatic cytosolic Bax, Bcl-2, cytochrome c, and calpain-mu expressions were measured by Western blot analysis. Hepatic mitochondrial glutathione levels were assessed by colorimetric assay. Compared with normal rats, rats receiving CCl4 alone showed profound DNA fragmentation associated with an increased cytosolic fraction of cytochrome c and calpain-mu protein expressions and a decreased mitochondrial glutathione level. In contrast, a decreased laddering of DNA fragmentation was noted in rats receiving CCl4 plus S. miltiorrhiza extract. The mitochondrial glutathione level was significantly increased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. Additionally, cytosolic caspase-3 activity and cytosolic fractions of Bax, Bcl-2, cytochrome c, and calpain-mu protein expressions were decreased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. The cytosolic caspase-8 activity in rats receiving CCl4 alone was no different from those receiving CCl4 plus S. miltiorrhiza extract. These results indicated that chronic administration of S. miltiorrhiza ameliorated CCl4-mediatd hepatic apoptosis in rats. This effect may be related to the antioxidant properties of S. miltiorrhiza.