Methotrexate is a chemotherapeutic agent. Nephrotoxicity is an important side effect of treatment with methotrexate. Zafirlukast is a cystenyl leukotriene antagonist that acts as an anti-inflammatory and antioxidant agent. The aim of this study was to analyze the nephrotoxicity induced by methotrexate in rats and to evaluate the possible ameliorative effect of zafirlukast. Ethanol (1ml/kg, orally once daily) and  zafirlukast (40mg/kg, orally once daily) were given for 10 days. Methotrexate (20mg/kg I.P, single injection) and, zafirlukast (40mg/kg, orally once daily) was given 5 days before methtrexate and then 5 days after the chemotherapeutic agent. Rats will be sacrificed after the 10th day from methotrexate intake. Rats given methotrexate alone had significantly higher MDA (malondialdehyde), lower reduced glutathione, catalase, superoxide dismutase in kidney tissue and higher blood urea nitrogen and serum creatinine levels than the control groups. Co-treatment of zafirlukast with methotrexate had an ameliorative effect on the previous parameters. Light & electronic microscopic pictures revealed that methotrexate caused marked degenerative changes in the kidney of rats. Restoration of the normal architecture of kidney tissues were observed in rats received methotrexate with zafirlukast. Thus, methotrexate can induce oxidative damage in rat kidney & zafirlukast has an ameliorative effect against this damage