Cisplatin nephrotoxicity has been recognized as a complex multifactorial process that includes oxidative stress pathways involved in apoptosis. Increased oxidative stress is one of the earliest features associated with the development of cisplatininduced nephropathy. Several investigators have demonstrated that Paclitaxel interaction of cisplatin with SH-groups leads to glutathione depletion, along with a decline of cellular antioxidant system and accumulation of reactive oxygen species or their products. Mitochondrial injury seems to play an important role in cisplatin-induced nephrotoxicity. Several functional and structural alterations of the mitochondria have been observed in cell cultures and in vivo animal models of cisplatin nephrotoxicity. This was evidenced by decreased mitochondrial mass with reduction of activities of oxidative phosphorylation complexes and manganese superoxide dismutase. This selectivity for mitochondria is probably caused by the accumulation of positively charged aquated complexes of cisplatin in the negatively charged inner space of the mitochondria. Thus, increased oxidative stress in cisplatin nephrotoxicity may be simply a consequence of disrupted respiratory chain and decreased antioxidant activity since mitochondria are a major source and target for damage by ROS. Oxidative stress and mitochondrial damage have been proposed as important factors that are involved in the activation of apoptotic pathway and cisplatin-induced cell death in vitro as well as in vivo. These events, together, result in the loss of renal function during cisplatin nephrotoxicity, triggering acute renal failure and tubular injury. A wide variety of antioxidants have been reported to exhibit protective effects against the deleterious effects of cisplatin-induced nephrotoxicity. As superoxide anions are the major injurious oxidant species generated by mitochondria, earlier studies have focused on the protective role for mitochondrial localized MnSOD in several models of free radicals-mediated cell injury. Tempol is a membrane-permeable radical scavenger which has SOD and catalase activities. Tempol has been reported experimentally to ameliorate oxidative stressmediated renal dysfunction and glomerular injury. Moreover, tempol ameliorated endothelial cell dysfunction in diabetic rats and reduced infarct size in an experimental model of regional myocardial ischemia/reperfusion. A phase I clinical trial in patients receiving whole brain radiotherapy suggested that tempol may be effective at preventing radiation-induced alopecia with only mild toxicity. Tempol, as an antioxidant, has been previously demonstrated to prevent injury induced by cisplatin using established renal epithelial cell line, LLC-PK1. However, no study has investigated the effect of tempol in an in vivo experimental model of cisplatin-induced nephrotoxicity in addition to mitochondrial role in its possible mediated protection. Therefore, the goal of the present study was directed to examine the implication of this membrane-permeable SOD-mimetic agent, tempol, in the prevention of mitochondrial dysfunction in cisplatin-induced nephrotoxicity. Moreover, the effect of tempol on cisplatin antineoplastic efficacy was investigated.