The effects of thymoquinone (TQ) on cisplatin-induced nephrotoxicity in mice and rats were studied. Oral administration of TQ (50 mg/L in drinking water) for 5 days before and 5 days after single injections of cisplatin (5 mg/kg, i.v., in rats and 7 or 14 mg/kg, i.p., in mice) greatly ameliorated cisplatin-induced nephrotoxicity in both species. In rats, i.v. cisplatin caused 4- and 5-fold elevations in serum urea and creatinine, a 235% increase in urine volume, a 41% increase in kidney weight, 8.5-fold decrease in creatinine clearance, and extensive histological damage 5 days after treatment. In mice, similar alterations in kidney function were observed. TQ-induced amelioration of cisplatin nephrotoxicity was evident by significant reductions in serum urea and creatinine and significant improvement in polyuria, kidney weight, and creatinine clearance. The protective effects of TQ against cisplatin-induced nephrotoxicity in the rat were further confirmed by histopathological examination. To evaluate the possible modification of the antitumor activity of cisplatin by TQ, we studied their interaction in Ehrlich ascites carcinoma (EAC) bearing mice. The results revealed that TQ potentiated the antitumor activity of cisplatin. The current study suggests that TQ may improve the therapeutic index of cisplatin.