Signal transducer and activator of transcription 3 (STAT3) plays a key role in body weight regulation and glucose homeostasis, 2 important determinants of metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genotype to affect MetS risk. In this study, we investigated the relationship between STAT3 polymorphisms and MetS phenotypes and determined potential interactions with dietary fatty acids. STAT3 polymorphisms (rs8069645, rs744166, rs2306580, rs2293152, and rs10530050), biochemical measurements, and dietary fat composition were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). STAT3 polymorphisms were not associated with MetS risk. However, minor G allele carriers for rs8069645, rs744166, and rs1053005 and major GG homozygotes for rs2293152 had increased risk of abdominal obesity compared with noncarriers [odds ratio (OR) = 2.22, P = 0.0005; OR = 2.08, P = 0.0017; OR = 2.00, P = 0.0033; and OR = 1.95, P = 0.028, respectively]. The number of risk alleles additively increased obesity risk (P = 0.0003). Dietary SFA intake exacerbated these effects; among all participants with the highest SFA intake (> or =15.5% of energy), individuals carrying >2 risk alleles had further increased risk of obesity (OR = 3.30; 95% CI = 1.50-7.28; P = 0.0079) compared with those carrying < or =1 risk allele. Interaction analysis confirmed this gene-nutrient interaction whereby increasing SFA intake was predictive of increased waist circumference (P = 0.038). In conclusion, STAT3 gene polymorphisms influenced the risk of abdominal obesity, which is modulated by dietary SFA intake, suggesting novel gene-nutrient interactions.