Objective: To investigate the inhibitory effect of matrine against hepatic ischemia-reperfusion injury (HIRI) in rats and the mechanism. Methods: HIRI in rats was induced by 60 min hepatic ischemia followed by 120 min reperfusion. Forty SD rats were equally randomized into sham operation group, HIRI model group (model group), low dose matrine (25 mg/kg) pretreatment plus HIRI model group (low dose matrine group) and high dose matrine (50 mg/kg) pretreatment plus HIRI model group (high dose matrine group). Rats in low and high dose matrine groups were injected with matrine of respective dose via the main trunk of the portal vein 30 min before hepatic ischemia, while those in sham operation group and model group received the same volume of normal saline by the same fashion. After the 120 min reperfusion, blood samples were drawn for measuring the serum levels of transaminases and inflammatory factors, and liver tissue samples were harvested for histopathological examination and analysis of hepatic cell apoptosis as well as determination of the protein expressions of TRAIL, BAX and activated caspase-3 (cleaved caspase-3). Results: The results of histopathological examination showed that there were liver injuries in all groups except in sham operation group, but the injuries varied in degree from severe to mild (model group>low dose matrine group>high dose matrine group). Compared with sham operation group, the serum levels of transaminases and inflammatory factors were significantly increased, the liver cell apoptosis was increased, and the protein expressions of TRAIL, BAX and cleaved caspase-3 were all up-regulated in the remaining groups (all P<0.05), but the changing amplitudes in above parameters in low and high dose group matrine groups were significantly milder than those in model group, and were more evident in high dose matrine group (all P<0.05). Conclusion: Matrine has inhibitory effect against HIRI in rats, and the mechanism may probably be associated with its inhibiting TRAIL expression and then reducing BAX and caspase-3 activation, and thereby suppressing liver cell apoptosis.