It is well recognized that reperfusion causes tissue damage in excess of that produced by ischemia alone. The present study was designed to test this and to evaluate the role of the calcium antagonist, diltiazem (400 µg/kg body weight administered intravenously over 95 min), in ischemia-reperfusion injury of the intestine. Intestinal ischemia was produced by occlusion of the superior mesenteric artery (SMA) with interruption of the collateral flow for 30 min. Reperfusion was established by declamping the SMA for 1 h, and mucosal injury was assessed using a grading scale from 0 to 5. The severity of mucosal damage increased significantly after 1 h of reperfusion, from a mean grade of 2.1 in the ischemia group to 3.8 in the ischemia-reperfusion group (p < 0.01). Diltiazem was effective in the amelioration of histologic changes of reperfusion injury and reduced the degree of mucosal injury from a mean grade of 3.8 in the ischemia-reperfusion group to 2.5 in the diltiazem group (p < 0.05). This study strongly suggests that calcium ions are involved in the pathogenesis of ischemia-reperfusion injury and that diltiazem attenuates this injury by preventing the intracellular calcium influx that occurs during reperfusion.