AbstractSerum uric acid (SUA), a causative agent for gout among others, is affected by both genetic and dietary factors, perhaps differentially by sex. We evaluated cross-sectional (SUA_base) and longitudinal (SUA_rate) associations of SUA with a genetic risk score (GRS), diet and sex. We then tested the interactive effect of GRS, diet and sex on SUA. Longitudinal data on 766 African-American urban adults participating in the Healthy Aging in Neighborhood of Diversity across the Lifespan study were used. In all, three GRS for SUA were created from known SUA-associated SNP (GRS_base (n 12 SNP), GRS_rate (n 3 SNP) and GRS_total (n 15 SNP)). Dietary factors included added sugar, total alcohol, red meat, total fish, legumes, dairy products, caffeine and vitamin C. Mixed-effects linear regression models were conducted. SUA_base was higher among men compared with that among women, and increased with GRS_total tertiles. SUA_rate was positively associated with legume intake in women (γ=+0·14; 95 % CI +0·06, +0·22, P=0·001) and inversely related to dairy product intake in both sexes combined (γ=−0·042; 95 % CI −0·075, −0·009), P=0·010). SUA_base was directly linked to alcohol consumption among women (γ=+0·154; 95 % CI +0·046, +0·262, P=0·005). GRS_rate was linearly related to SUA_rate only among men. Legume consumption was also positively associated with SUA_rate within the GRS_total’s lowest tertile. Among women, a synergistic interaction was observed between GRS_rate and red meat intake in association with SUA_rate. Among men, a synergistic interaction between low vitamin C and genetic risk was found. In sum, sex–diet, sex–gene and gene–diet interactions were detected in determining SUA. Further similar studies are needed to replicate our findings.