Abstract—The peroxisome proliferator activated receptor (PPAR&ggr;) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R+A+). Rosiglitazone decreased systolic (138±5 versus 128±5 mm Hg) and mean blood pressure (145±5 versus 126±7 mm Hg) of R+A+mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R+A+mice when compared with littermate controls (RA−). There were no effects of rosiglitazone on RA−mice; however, relaxation to acetylcholine (49±10 versus 82±9% at 100 &mgr;mol/L) and nitric oxide (51±11 versus 72±6% at 10 &mgr;mol/L) was significantly improved in treated R+A+mice. Rosiglitazone treatment of R+A+mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R+A+and RA−mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPAR&ggr;-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitorN&ohgr;-nitro-l-arginine methyl ester (200 &mgr;mol/L) or the PPAR&ggr; antagonist bisphenol A diglycidyl ether; 4,4′-isopropylidenediphenol diglycidyl ether (100 &mgr;mol/L). These data suggest that in addition to potential genomic regulation caused by PPAR&ggr; activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.