Background: Race differences in body composition and fat distribution may in part explain the differences in insulin sensitivity and the disproportionate burden of type 2 diabetes in African Americans. Objective: To determine if differences in body composition and fat distribution explain race differences in insulin sensitivity and identify obesity measures that were independently associated with insulin sensitivity. Methods: Participants were 113 lean, overweight, and obese African-American and Caucasian-American adults without diabetes. Skeletal muscle insulin sensitivity was determined using a hyperinsulinemic-euglycemic clamp (SIClamp, insulin rate:120 mU/m2/min). Subcutaneous abdominal adipose tissue (SAAT), intra-abdominal adipose tissue (IAAT), and liver fat were measured by MRI; leg fat, total fat, and lean mass were measured by DXA. Results: Race-by-adiposity interactions were significant in cross-sectional analyses utilizing multiple linear regression models for SIClamp (P < 0.05); higher BMI, fat mass, SAAT, leg fat, and liver fat were associated with lower SIClamp in Caucasian Americans but not African Americans. Race-by-IAAT interaction was not significant (P = 0.65). A central fat distribution (SAAT adjusted for leg fat) was associated with lower SIClamp in African Americans (β =-0.45, SE = 0.11, P < 0.001) but not Caucasian Americans (β =-0.42, SE = 0.30, P = 0.17). A peripheral fat distribution (leg fat adjusted for IAAT/SAAT) was associated with a higher SIClamp in African Americans (β = 0.11, SE = 0.05, P = 0.02) but lower SIClamp in Caucasian Americans (β =-0.28, SE = 0.14, P = 0.049). Lean mass was inversely associated with SIClamp in African Americans (β =-0.05, SE = 0.03, P = 0.04) but not Caucasian Americans (β = 0.08, SE = 0.05, P = 0.10) in the model for leg fat. Conclusions: Measures of overall adiposity were more strongly associated with SIClamp in Caucasian Americans, whereas body fat distribution and lean mass showed stronger correlations with SIClamp in African Americans. Insulin sensitivity may have a genetic basis in African Americans that is reflected in the pattern of body fat distribution. These findings suggest a race-specific pathophysiology of insulin resistance, which has implications for the prevention of diabetes and related cardiometabolic diseases.