The purpose of this study was to investigate the protective effects of the calcium channel blocker verapamil on warm ischemia-reperfusion injury to the liver using a rat model. Ischemia of the left and median lobes was created by total inflow occlusion for 60 min followed by 24 hr of reperfusion. Hepatocell injury was assessed by the release of liver enzymes [alanine aminotransferase (ALT) and lactic dehydrogenase (LDH)], reduced (GSH) and oxygenated (GSSG) plasma glutathione and total biliary glutathione. Hepatocyte function was quantitated by measuring bile flow. Rats were randomized to one of two groups: pretreatment with iv verapamil (0.3 mg/kg) or iv normal saline (controls). Verapamil significantly increased bile flow and GSH efflux while decreasing plasma ALT and LDH compared to those in controls 24 hr after liver ischemia-reperfusion (LIR). A significant correlation existed between bile flow and biliary GSH efflux at 1 but not 24 hr after LIR, suggesting that early LIR injury is mediated predominantly by generation of oxygen free radicals. Liver enzyme elevation and bile flow were inversely correlated at 24 but not 1 hr after injury. We conclude that verapamil significantly protects the liver against warm LIR injury. The minimal protective effect of verapamil on early liver ischemia-reperfusion demonstrates that verapamil does not prevent the early generation of oxygen radicals upon reperfusion. However, the significant restoration of biliary GSH efflux and hepatocyte protection at 24 hr suggests involvement of calcium ions in late hepatocyte injury. Verapamil's protective effects may be related to attenuating pathophysiologic events occurring beyond 1 hr of reperfusion. Future studies investigating the protective effects of verapamil on warm LIR injury should be carried out for at least 24 hr postreperfusion.