The cardiovascular benefits of light to moderate red wine consumption often have been attributed to its polyphenol constituents. However, the acute dose-related hemodynamic, vasodilator and sympathetic neural effects of ethanol and red wine have not been characterized and compared in the same individual. We sought to test the hypotheses that responses to 1 and 2 alcoholic drinks differ; and that red wine with high polyphenol content elicits greater effect than ethanol alone. Thirteen volunteers (24-47yrs, 7 men) drank wine, ethanol, and water in a randomized, single-blind trial on 3 occasions, 2 weeks apart. One drink of wine and ethanol increased blood-alcohol to 38±2 and 39±2mg/dL respectively, and 2 drinks to 72±4 and 83±3mg/dL. Wine quadrupled plasma resveratrol (P<0.001) and increased catechin (P<0.03). No intervention affected blood pressure. One drink had no heart rate effect but 2 drinks of wine did (+5.7±1.6 beats/min; P<0.001). Cardiac output fell 0.8±0.3L/min after one drink of ethanol and wine (all P<0.02), but increased after 2 drinks of ethanol (+0.8±0.3L/min) and wine (+1.2±0.3L/min)(P<0.01). One alcoholic drink did not alter muscle sympathetic nerve activity (MSNA), while 2 drinks increased MSNA by 9-10 bursts/min (P<0.001). Brachial-artery diameter increased after both one and two alcoholic drinks (P<0.001). No beverage augmented, and the second wine dose attenuated (p=0.02) flow-mediated vasodilatation. One drink of ethanol dilates the brachial artery without activating sympathetic outflow whereas 2 drinks increase MSNA, heart rate, and cardiac output. These acute effects, which exhibit a narrow dose response, are not modified by red wine polyphenols.