Previous studies have shown that the synthesis of renal CYP-derived eicosanoids is downregulated in genetic or high fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a PPAR-agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg/kg/day for 4 weeks) significantly reduced plasma insulin, triglyceride and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared to lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 µM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37%±11%) compared to lean controls (67%±9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 µM of acetylcholine in obese Zucker rats (69%±4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid (PPOH) attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared to obese Zucker rats. These results demonstrate that the PPAR- agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.