Aims: Conficting results have been reported on the association of fat-free mass (FFM) and insulin resistance (IR). This study sought to test the association of FFM and IR by indexing FFM to avoid collinearity with fat mass. Methods: This cross-sectional study comprised 11,284 volunteers, aged 38–79 years. Body composition was assessed by multi-frequency bioelectrical impedance. FFM indexed to body surface area (FFMbsa) was calculated. IR and impaired glucose tolerance (IGT) were estimated with homeostatic model assessment of insulin resistance index (HOMA-IR) and 2-h oral glucose tolerance test (2h-OGTT), respectively. Results: Percent body fat decreased from the 1st to the 5th quintile of FFMbsa in both women (Eta2=0.166) and men (Eta2=0.133). In women, fasting insulin (Eta2=0.002), glucose (Eta2=0.006), and HOMA-IR (Eta2=0.007) increased slightly, but 2-h plasma glucose (2-h PG) was similar across the quintiles of FFMbsa. In men, fasting insulin and HOMA-IR were similar across the quintiles of FFMbsa, whereas fasting glucose increased slightly (Eta2=0.002) and 2-h PG decreased (Eta2=0.005) toward the highest quintile of FFMbsa. The higher the odds ratio for IR, the greater the FFMbsa in both sexes. Diferently, FFMbsa did not afect the odds of IGT in women, while in men the odds ratio for IGT was lower in the 5th quintile compared with the 1st quintile of FFMbsa. Conclusions: Higher odds of IR associated with greater FFMbsa contrasted with lower odds of IGT associated with greater FFMbsa. IR may be misdiagnosed by HOMA-IR in adults with greater fat-free mass.