Exogenous bilirubin (BR) substitutes for the protective effects of heme oxygenase (HO) in several organ systems. Our objective was to investigate the effects of exogenous BR in an in vivo. model of ischemia reperfusion injury (IRI) in the rat kidney. Four groups of male Sprague Dawley rats were anesthetized and treated: (1) 5 mg/kg IV BR, 1 h prior to ischemia and 6 h reperfusion (2) Vehicle 1 h prior to ischemia and 6 h reperfusion (3) 20 mg/kg IV BR, 1 h prior to and during ischemia (4) Vehicle 1 hr prior to and during ischemia. Bilateral renal clamping (30 min) was followed by 6 h reperfusion. IV infusion of 5 mg/kg BR achieved target serum levels at 6 h post ischemia (31±9µmol/L). Infusion of 20 mg/kg BR reached 50±22 µmol/L at the end of ischemia, and a significant improvement was seen in serum creatinine at 6 hours (1.07±28 mg/dL vs. 1.38±0.18 mg/dL, p=0.043). GFR, estimated renal plasma flow, fractional excretion of electrolytes, and renal vascular resistance were not significantly improved in BR treated groups. Histologic grading demonstrated a trend toward preservation of cortical proximal tubules in rats receiving 20 mg/kg IV BR compared to control; however, neither BR dose provided protection against injury to the renal medulla. At the doses administered, IV BR did not provide complete protection against IRI in vivo.. Combined supplementation of both BR and CO may be required to preserve renal blood flow and adequately substitute for the protective effects of HO in vivo.