Zofenopril ameliorates experimental cardiac ischemia/reperfusion (IR) injury in animal models and exhibits beneficial cardiovascular effects in patients with myocardial infarction. The objective of the present research was to investigate whether zofenopril can protect against renal IR injury. Rats were divided into 4 experimental groups: (a) control, (b) IR (60 min of ischemia followed by 24 hr of reperfusion), (c) zofenopril (15 mg/kg/day for 2 days), and (d) zofenopril+IR. All of the rats underwent right nephrectomy, and the rats in the IR and zofenopril+IR groups also underwent IR. Then the left kidneys were removed for biochemical analyses and microscopic examination. There were no abnormalities in the biochemical and microscopic findings in the preoperative right kidneys. The lipid peroxidation, protein oxidation, and nitric oxide levels as well as xanthine oxidase and myeloperoxidase activities were increased and the catalase and superoxide dismutase activities were decreased in the IR group; zofenopril treatment prevented these changes (p < 0.05). In the IR group, the kidney sections showed severe acute tubular damage including brush border loss, nuclear condensation, cytoplasmic swelling, and loss of nuclei; in the zofenopril+IR group, the normal glomerular morphology was preserved and there was slight edema of the tubular cells. The renal damage score was significantly reduced in the zofenopril+IR group vs the IR group (p < 0.05). In conclusion, IR injury caused oxidative damage in renal tissue and zofenopril prevented this IR injury.