Diabetic nephropathy (DN) is an important microvascular complication of diabetes and one of the main causes of end stage renal disease. The protective effect of lycopene against streptozotocin (STZ) induced diabetic nephropathy and oxidative stress in rats was evaluated. Seventy two male albino rats were divided into four groups. Group I (normal group): rats administered buffer citrate. Group II (DN group): rats received a single intraperitoneal (i.p) injected dose of STZ (50 mg/kg b.wt). Group III (DN + insulin treated group): diabetic nephropathy rats treated with insulin (2U/rat/day/i.p). Group IV (DN + lycopene treated group): diabetic nephropathy rats treated with lycopene (20 mg/kg b.wt/day/orally). The obtained results showed a significant increase in serum glucose, urea, creatinine and kidney tissue L-MDA concentrations with upregulation of NF-kB gene expression in diabetic nephropathy induced rats. However, SOD activity and GSH level of kidney tissues were markedly decreased. Administration of lycopene to DN induced rats caused a significant improvement of all previous parameters towards their normal range. These results suggested that, lycopene treatment may have a protective effect against STZinduced diabetic nephropathy and oxidative stress in rats through free radical scavenging and antiinflammatory activity as well as regenerating endogenous antioxidant defense system mechanisms.