The clinical use of cisplatin is highly limited, because of its renal toxicity. In this study, the protective effect of grape seed proanthocyanidin extract (GSPE) against cisplatin-induced nephrotoxicity is investigated in rats. Results showed that DNA qualitative analysis indicated an increase in the instability of the DNA purified from the cisplatin exposed kidney cells. Agarose gel electrophoresis revealed DNA damage in the form of smearing as well as ladder like fragmentation of the kidney genomic DNA. Cisplatin produced different RAPD patterns compared to control. Deletion of bands for the amplified DNA extracted from cisplatin treated rats was the most common outcome. Treatment with cisplatin decreased albumin, and increased urea and creatinine. Cisplatin significantly increased the level of kidney free radicals, and decreased the glutathione content and the activities of the antioxidant enzymes. The presence of GSPE with cisplatin significantly alleviated its nephrotoxicity. In conclusion, the present study showed that cisplatin induced damage in the kidney genomic DNA, lipid peroxidation, inhibition of antioxidant enzymes and alterations of biochemical parameters in plasma and kidney of rats. While, GSPE treatment protected against the toxic effects induced by cisplatin. Thus, GSPE may be used to prevent toxicity during chemotherapeutic treatment with cisplatin.