['Recent experimental work in mice has demonstrated that leptin is synthesized by muscle cells. As this latter tissue is the main target for insulin-estimulated glucose disposal, we hypothesized that the muscular and fat-free mass (FFM) compartments might influence serum leptin levels in humans through increased insulin resistance.', 'We evaluated body composition (through bioelectric impedance and anthropometrical parameters), insulin resistance (using the fasting insulin resistance index (FIRI) and insulin sensitivity (S(I)) from the minimal model analysis) and leptin levels in 140 men and 114 women.', 'Serum insulin, FIRI and leptin levels were significantly increased in men in the highest quintile of FFM. Leptin levels positively correlated with FFM in men (r=0.24, P=0004) but not in women (r=0.02, P=not significant). With weight gain, however, approximately 25% of the additional weight is lean mass, so that obese people have higher fat-free mass than lean people. Hence, we performed a multiple linear regression analysis in a stepwise manner to predict leptin levels, in which fat mass (FM), FFM, and FIRI, but not age or waist-to-hip ratio (WHR) independently contributed to 32%, 6% and 3% of the variance in serum leptin levels in men. In women, FM (49%), FIRI (3.6%) and WHR (2.4%), but not FFM or age explained this variance. In a sample of 40 subjects, S(I) and leptin correlated with mid-arm muscle circumference (r=-0.51, P=0.03 and r=0.53, P=0.02) and mid-arm muscle area (r=-0.52, P=0.03 and r=0.53, P=0.02) in men (n=17) but not in women (n=23).'] Does the fat-free mass compartment influence serum leptin in men?