Warm ischemia and reperfusion (WI/R) results in the release of destructive proinflammatory cytokines and oxygen free radicals, which in turn cause injury to the liver. Apoptosis is regarded as the central mechanism of liver injury during WI/R. Oxymatrine, an extract from a traditional Chinese herb, Sophora flavescens Ait, has been widely used for the treatment of chronic hepatitis, by virtue of its anti-inflammatory and anti-apoptotic activity. The objective of this study was to investigate whether administration of oxymatrine could protect livers against WI/R. The experimental design consisted of three groups of rats (each group contained 10 Wistar rats): one group were treated by sham-operation; the second (control) group with WI/R were administrated saline, and the third group, rats with WI/R, were administered oxymatrine). Oxymatrine was intravenously administered before a 30-minute period of ischemia. Blood samples were collected for biochemical assay. Liver samples taken at different time points underwent histological examination for detection of apoptotic cells, and Western blotting analysis for Fas and Fas ligand, the key factors in the upper apoptotic pathways. Histologic alteration of the liver was attenuated in oxymatrine-treated rats, and the serum levels of AST and ALT were significantly (P < 0.01) reduced (73% and 61%, respectively). Oxymatrine significantly inhibited cell apoptosis, as examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), and it reduced the apoptotic index by 65% (P < 0.05%) as detected by flow cytometry. The anti-apoptotic activity of oxymatrine depends mainly on downregulation of Fas and Fas ligand. The results of this study indicate that oxymatrine may represent a potent drug to protect the liver against WI/R injury.