Methotrexate (Mtx), used for its anticancer and immunsuppresive properties, is known to be a nephrotoxicagent. We aimed to investigate the effects of lycopene (Lyc) alone or combined with melatonin (Mel) on Mtxinducednephrotoxicity since both of these agents have antioxidant and anti-inflammatory effects. Nephrotoxicitywas induced by intraperitoneal administration of methotrexate at a dose of 20 mg/kg. Treatment both with Lycalone and Lyc combined with Mel provided significant reduction in tumor necrosis factor-alpha, interleukin1-beta and ceruloplasmin levels in Mtx administered rats. Hovewer, Lyc combined with Mel provided a significantreduction also in NO levels. Hstopathological examination showed that there was an obvious improvement inthe degenerative changes compared to Mtx administrated group with the Lyc combined Mel group giving bestprotection. In conclusion Lyc alone and combined with Mel provided significant improvement against renaldamage caused by Mtx, preseumably via antioxidant and anti-inflammatory activities.