Controversy exists regarding the relative importance of adiposity, physical fitness, and physical activity in the regulation of insulin-stimulated glucose disposal. To address this issue, we measured insulin-stimulated glucose disposal [mg. kg fat-free mass (FFM)(-1). min(-1); oxidative and nonoxidative components] in 45 nondiabetic, nonobese, premenopausal women (mean +/- SD; 47 +/- 3 yr) by use of hyperinsulinemic euglycemic clamp (40 mU. m(-2). min(-1)) and [6,6-2H2]glucose dilution techniques. We also measured body composition, abdominal fat distribution, thigh muscle fat content, maximal oxygen consumption (VO2 max), and physical activity energy expenditure ((2)H(2)(18)O kinetics) as possible correlates of glucose disposal. VO2 max was the strongest correlate of glucose disposal (r = 0.63, P < 0.01), whereas whole body and abdominal adiposity showed modest associations (range of r values from -0.32 to -0.46, P < 0.05 to P < 0.01). A similar pattern of correlations was observed for nonoxidative glucose disposal. None of the variables measured correlated with oxidative glucose disposal. The relationship of VO2 max to glucose disposal persisted after statistical control for FFM, percent body fat, and intra-abdominal fat (r = 0.40, P < 0.01). In contrast, correlations of total and regional adiposity measures to insulin sensitivity were no longer significant after statistical adjustment for VO2 max. VO2 max was the only variable to enter stepwise regression models as a significant predictor of total and nonoxidative glucose disposal. Our results highlight the importance of VO2 max as a determinant of glucose disposal and suggest that it may be a stronger determinant of variation in glucose disposal than total and regional adiposity in nonobese, nondiabetic, premenopausal women.