Good insulin sensitivity is independently associated with a low risk for coronary heart disease, but it is unclear whether this risk factor differs between men and women. We compared insulin sensitivity of glucose uptake directly in muscle and heart tissues between healthy women (age 29 +/- 2 years, body mass index [BMI] 22 +/- 1 kg/m2, VO2max 39 +/- 4 ml.kg-1.min-1) and men matched for age (31 +/- 2 years), BMI (23 +/- 1 kg/m2), and VO2max (44 +/- 3 ml.kg-1.min-1) using [18F]fluoro-2-deoxy-D-glucose and positron emission tomography under hyperinsulinemic (insulin infusion rate 1 mU.kg-1.min-1) normoglycemic conditions. Whole body insulin sensitivity was 41% greater in women (52 +/- 6 mumol.kg body wt-1.min-1) than in men (37 +/- 3 mumol.kg body wt-1.min-1, P < 0.05). This difference was explained by a 47% greater rate of glucose uptake by femoral muscles (113 +/- 10 vs. 77 +/- 7 mumol.kg muscle-1.min-1, women vs. men, P < 0.01). Insulin-stimulated glucose uptake rates in the heart were similar in women (738 +/- 58) and men (749 +/- 62 mumol.kg muscle-1.min-1). Femoral muscle insulin sensitivity was closely correlated with whole body insulin sensitivity (r = 0.84, P < 0.001). Gender and VO2max together explained 68% of the variation in femoral muscle glucose uptake. We conclude that women are more sensitive to insulin than equally fit men because of enhanced muscle but not heart insulin sensitivity.