Fat mass and obesity-associated (FTO) is the strongest genetic determinant of obesity identified to date. Dietary fat is a key environmental factor that may interact with genotype to affect risk of obesity and metabolic syndrome (MetS). This study investigated associations among FTO rs9939609, obesity measures, and MetS phenotypes in adults and determined potential modulation by dietary fat intake at baseline and after a 7.5-y follow-up when MetS cases and controls were selected. FTO rs9939609 genotype, biochemical, dietary, and lifestyle measurements were determined in the LIPGENE-SU.VI.MAX study In = 1754). FTO rs9939609 A allele carriers had a higher risk of being overweight or obese (OR = 1.66 (95% Cl: 1.07, 2.571; P 0.02] and of having a larger abdominal circumference [OR = 1.42(95% Cl: 1.01, 1.99); P = 0.04] compared with the TT homozygotes. These associations were independent of physical activity and energy intake and were maintained over the follow-up period, particularly in the MetS individuals. High dietary SFA intake (>= 15.5% energy) and a low dietary PUFA:SFA intake ratio (<0.38) further accentuated the risk of having a BMI >= 25 kg/m(2) and being abdominally obese. Non-risk allele carriers appeared to be unresponsive to dietary SFA intake or to the dietary PUFA:SFA intake ratio with respect to obesity measures. In conclusion, FTO rs9939609 was associated with obesity measures, especially in those with the MetS, which was further exacerbated by high dietary SFA intake at baseline and 7.5 y later. These data indicate important novel modulation of genetic risk by dietary fat exposure in individuals with increased cardiometabolic risk. J. Nutr. 142: 824-831, 2012.