These studies were done to examine the effects of body composition, resting energy expenditure (REE), sex and fitness on basal and insulin regulated FFA and glucose metabolism. We performed 137 experiments in 101 non-diabetic, pre-menopausal women and men, ranging from low normal weight to Class III obese (BMI 18.0-40.5 kg/m²). Glucose flux was measured using [6-²H₂]glucose and FFA kinetics with [9,10-³H]oleate under either basal (74 experiments) or euglycemic, hyperinsulinemic (1.0 mU/kg FFM/min) clamp conditions (63 experiments). Results: Consistent with our previous findings, REE and sex independently predicted basal FFA flux, whereas fat free mass was the best predictor of basal glucose flux; in addition, percent body fat was independently and positively associated with basal glucose flux (total R²=0.52, P < 0.0001). Insulin suppressed lipolysis remained significantly associated with REE (r = 0.25, P < 0.05), but percent body fat also contributed (total adjusted R² = 0.36 p<0.0001), whereas sex was not significantly related to insulin-suppressed FFA flux. Glucose disposal during hyperinsulinemia was independently associated with peak VO₂, percent body fat and FFA concentrations (total R² = 0.63, P < 0.0001), but not with sex. We conclude that basal glucose production is independently related to both FFM and body fatness. In addition, hyperinsulinemia obscures the sex differences in FFA release relative to REE, but brings out the effects of fatness on lipolysis.