Oxidative stress and apoptosis are important factors in the etiology of renal ischemia-reperfusion (IR) injury. The current study tested the hypothesis that the cell permeable SOD mimetic, Manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTmPyP) protects the kidney from IR mediated oxidative stress and apoptosis in vivo. Male Sprague-Dawley (SD) rats (175-220g) underwent renal IR by bilateral clamping of the renal arteries for 45 minutes followed by reperfusion for 24 hours (IR). To examine the role of reactive oxygen species (ROS) in renal IR injury, a subset of animals were treated with either saline vehicle (IR Veh) or MnTMPyP (IR Mn) (5mg/Kg, i.p.) 30 minutes prior to and 6 hours post surgery. MnTMPyP significantly attenuated the IR-mediated increase in serum creatinine levels and decreased tubular epithelial cell damage following IR. MnTMPyP also decreased TNF- levels, gp^91phox and lipid peroxidation following IR. Further, MnTMPyP inhibited the IR-mediated increase in apoptosis and caspase-3 activation. Interestingly, although MnTMPyP did not increase expression of the anti-apoptotic protein Bcl-2, it decreased the expression of the pro-apoptotic genes Bax and FasL. These results suggest that MnTmPyP is effective in reducing apoptosis associated with renal IR injury and that multiple signaling mechanisms are involved in ROS mediated cell death following renal IR injury.