This study addressed the role of blood flow and nitric oxide in leg glucose uptake. Seven subjects (5 men, 2 women) were studied during conditions of resting blood flow and increased blood flow, achieved by infusion of the nitric oxide (NO) donor sodium nitroprusside (SNP) into the femoral artery. Femoral arterial and venous blood samples were obtained and blood flow was determined by infusion of indocyanine green dye. SNP infusion significantly increased leg blood flow (769 +/- 103 v 450 +/- 65 mL. min(-1). leg(-1), P <.001), but did not affect arterial (4.68 +/- 0.13 mmol/L control, 4.63 +/- 0.09 mmol/L SNP) or venous (4.60 +/- 0.14 mmol/L control, 4.54 +/- 0.10 mmol/L SNP) glucose concentrations. Glucose uptake was significantly (P <.01) higher during SNP infusion (65 +/- 6 micromol. min(-1). leg(-1)) than during the basal period (34 +/- 6 micromol. min(-1). leg(-1)), whereas lactate release was unaffected (rest, 45 +/- 11 micromol. min(-1). leg(-1); SNP, 42 +/- 14 micromol. min(-1). leg(-1)). We conclude that blood flow and/or NO increase basal leg glucose uptake.