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 grape seed proanthocyanidins extract (GSPE) against streptozotocin (STZ) induced diabetic nephropathy and oxidative stress in rats was evaluated. Seventy two male albino rats 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 + GSPE treated group): diabetic nephropathy rats treated with GSPE (250 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 GSPE to DN induced rats caused a significant improvement of all previous parameters towards their normal ranges. These results suggested that, GSPE treatment may have a therapeutic effect against STZ-induced diabetic nephropathy and oxidative stress in rats through free radical scavenging and anti-inflammatory activity as well as regenerating endogenous antioxidant defense system mechanisms.