In this cross-sectional study of a large sample of US adults of self-identified African and European race groups, we observed that the often-reported FTO obesity risk alleles were not associated with obesity for the Black group while controlling for race and psychosocial variables and that association between obesity and cardiometabolic disease varied by sex for White participants with rs1558902. Here, FTO is linked to obesity due to melanocortin 4 receptor deficiency.