This study investigated the effect of insulin on plasma and muscle creatine accumulation and limb blood flow in humans after creatine administration. Seven men underwent a 300-min euglycemic insulin clamp combined with creatine administration on four separate occasions. Insulin was infused at rates of 5, 30, 55, or 105 mU. m-2. min-1, and on each occasion 12.4 g creatine was administered. During infusion of insulin at rates of 55 and 105 mU. m-2. min-1, muscle total creatine concentration increased by 4.5 +/- 1.4 (P < 0. 05) and 8.3 +/- 1.0 mmol/kg dry mass (P < 0.05), and plasma creatine concentrations were lower at specific time points compared with the 5 mU. m-2. min-1 infusion rate. The magnitude of increase in calf blood flow (plethysmography) was the same irrespective of the rate of insulin infusion, and forearm blood flow increased to the same extent as the three highest infusion rates. These findings demonstrate that insulin can enhance muscle creatine accumulation in humans but only when present at physiologically high or supraphysiological concentrations. This response is likely to be the result of an insulin-mediated increase in muscle creatine transport rather than creatine delivery.