The prevalence of type 2 diabetes is higher among African Americans (AA) vs. European Americans (EA), is highest at middle age, and is related to obesity. This study was conducted to test the hypothesis that the association of adiposity (percent body fat (%fat)) with indexes of insulin sensitivity (S(I)) and β-cell function would differ with ethnicity and age. Subjects were 168 healthy, normoglycemic AA and EA girls and women aged 7-12 years, 18-32 years, and 40-70 years. An intravenous glucose tolerance test (IVGTT) was used to assess indexes of insulin secretion and action: S(I), acute C-peptide secretion (X0); basal, first-phase, second-phase, and total β-cell responsivity to glucose (PhiB, Phi1, Phi2, and Phi(TOT), respectively); and the disposition index (DI = S(I) × Phi(TOT)). %Fat was assessed with dual energy X-ray absorptiometrys. Adiposity was significantly associated with S(I) among EA (-0.57, P < 0.001) but not AA (-0.20, P = 0.09). Adiposity appeared stimulatory to β-cell function in the two groups of younger subjects and in EA, but inhibitory in postmenopausal women, particularly AA postmenopausal women. Among AA postmenopausal women, %fat was inversely associated with Phi1 (r = -0.57, P < 0.05) and Phi(TOT) (r = -0.68, P < 0.01). These results suggest that the impact of adiposity on insulin secretion and action differs with age and ethnicity.