The authors hypothesized that carvedilol controlled-release plus lisinopril combination therapy (C+L) would increase endothelial function and decrease oxidative stress to a greater extent than hydrochlorothiazide plus lisinopril combination therapy (H+L) in obese patients with hypertension. Twenty-five abdominally obese patients (aged 54.4±7.3 years; 14 women) with hypertension/prehypertension were enrolled in a 7-month (two 3-month treatment periods separated by a 1-month washout), randomized, double-blind, controlled, crossover clinical trial comparing C+L vs H+L. Endothelial function, measured by digital reactive hyperemic index (RHI), circulating oxidized low-density lipoprotein (oxLDL), 8-isoprostane, and asymmetric dimethylarginine (ADMA) were obtained at baseline, post-period 1, post-washout, and post-period 2. Analyses were adjusted for baseline measurements by analysis of covariance, with robust variance estimation for confidence intervals and P values. C+L treatment compared to H+L treatment significantly improved RHI (0.74, 95% confidence interval, 0.31-1.19, P=.001). This difference persisted after adjustment for the change in systolic blood pressure. No significant treatment differences were observed for oxLDL, 8-isoprostane, or ADMA. These data provide evidence that independent of blood pressure-lowering, C+L therapy improves endothelial function to a greater extent than H+L therapy. Levels of oxidative stress were not significantly different between treatments, suggesting that other mechanisms may be responsible for the improvement in endothelial function.