During systemic hyperinsulinemia in man, skeletal muscle vasodilation has consistently been demonstrated. However, most studies that have examined the vascular effect of local hyperinsulinemia have reported either no effect or only weak vasodilation, and all of these have been open in design. The present studies were designed in a double blind, placebo-controlled manner to evaluate the direct (local) vascular effect of insulin alone and in association with physiological concentrations of D-glucose. Forearm blood flow was measured in 17 healthy male volunteers by bilateral venous occlusion forearm plethysmography. Brachial artery infusions of 1 mU/min insulin, 5 mU/min insulin, or vehicle were administered for 90 min on 3 separate study days in random order. The higher dose of insulin was associated with weak (20%) vasodilation compared with placebo (F = 5.75 and P < 0.01, by ANOVA). When this protocol was repeated with intraarterial coinfusion of D-glucose, significant augmentation of the vascular effect was demonstrated (47% vasodilation). No augmentation of insulin-mediated vasodilation was observed with coinfusion of L-glucose, the metabolically inactive stereoisomer. These data suggest that local uptake of D-glucose by insulin-sensitive tissues is an important determinant of insulin-mediated vasodilation.