Background: Improvement in endothelial function is predicted to improve insulin sensitivity. We hypothesize efonidipine improves endothelial function by enhancing insulin sensitivity. Methods: We administered placebo or efonidipine 40-80 mg daily for 8 weeks to 39 patients with mild to moderate hypertension. This study was randomized, double-blind, placebo-controlled, crossover in design. Data are expressed as mean짹SEM. Results: Compared with placebo, efonidipine significantly reduced systolic and diastolic blood pressure by 9짹1% (p<0.001) and 9짹1% (p<0.001), respectively, however, it did not change lipid profiles. Compared with placebo, efonidipine significantly improved flow-mediated dilator response to hyperemia by 20짹7% (p<0.001) and reduced plasma malondialdehyde levels by 7짹3% (p=0.022). When compared with placebo, efonidipine significantly increased plasma adiponectin levels by 15짹4% (p=0.011) and increased insulin sensitivity (assessed by QUICKI) by 3짹2% (p=0.217). There were significant correlations between percent changes in flow-mediated dilation and percent changes in malondialdehyde levels (r= -0.501, p=0.001) or QUICKI (r= 0.460, p=0.003). Multivariate regression analysis showed that only changes in malondialdehyde (b= -0.839, p=0.009) or QUICKI (b= 1.329, p=0.013) persisted as an independent predictor of changes in flow-mediated dilation. There were significant correlations between percent changes in adiponectin levels and percent changes in QUICKI (r= 0.373, p=0.020) or HDL cholesterol (r= 0.410, p=0.009). Multivariate regression analysis showed that only changes in HDL cholesterol (b= 0.413, p=0.011) or QUICKI (b= 0.464, p=0.070) persisted as an independent predictor of changes in adiponectin levels. Conclusions: Efonidipine therapy significantly improved percent flow-mediated dilator response to hyperemia and reduced oxidant stress marker levels and increased adiponectin levels and improved insulin sensitivity in patients with hypertension.