Abstract: Nephrotoxicity is a dose-limiting factor in clinical use of cisplatin. The changes in renal haemodynamics were suggested to play a role in cisplatin-induced nephrotoxicity. The aim of the present study was to investigate the effect of modulation of nitric oxide on the severity of cisplatin-induced nephrotoxicity using an experimental rat model. A nitric oxide precursor, L-arginine and an inhibitor of nitric oxide synthase, L-NAME were used. After six days of cisplatin injection, acute nephrotoxicity was demonstrated by a marked increase in serum creatinine and blood urea nitrogen. Histological examination of the kidneys confirmed the occurrence of renal damage. Moreover, cisplatin induced an increase in the level of lipid peroxides and oxidized glutathione and a depletion of reduced glutathione. The activities of the antioxidant enzymes glutathione peroxidase and superoxide dismutase were also lowered. Besides, there was a reduction in the kidney total nitrate/nitrite levels. L-arginine significantly attenuated the oxidative stress and nephrotoxic effect of cisplatin. On the other hand, L-NAME was found to aggravate cisplatin nephrotoxicity. In conclusion, the decrease in the kidney nitric oxide level contributes, at least in part, in the mechanism underlying the nephrotoxicity of cisplatin. Furthermore, L-arginine shows nephroprotective effects and might be useful in improving the therapeutic index of cisplatin.