Whether the FTO polymorphisms interact with environmental factors has not yet been evaluated in associations with metabolic syndrome (MS) risk. The present study investigated the association of the FTO rs9939609 genotypes, body mass index (BMI), and lifestyle-related factors including smoking, alcohol drinking, physical activity, and diet with MS incidence. A population-based prospective cohort study comprised 3,504 male and female Koreans aged 40 to 69 years. At the beginning of the study, all individuals were free of MS and known cardiovascular disease. Incident cases of MS were identified by biennial health examinations during a follow-up period from April 17, 2003 to April 15, 2009. Pooled logistic regression analysis was applied to obtain relative odds (RO) of MS with its 95% confidence interval (CI). After controlling for potential MS risk factors, we observed no association between the rs9939609 genotypes and MS incidence. In analysis stratified by BMI, however, carriers with the FTO risk allele whose BMI is 29 kg/m² or greater showed an approximately 6-fold higher RO (95% CI: 3.82 to 9.30) compared with non-carriers with BMI less than 25 kg/m². In particular, the association between the rs9939609 variants and MS risk was significantly modified by high BMI ( P -value for interaction < 0.05). Such significant interaction appeared in associations with central obesity and high blood pressure among the MS components. Because carriers of the FTO risk alleles who had BMI of 29 kg/m² or greater are considered a high risk population, we suggest that they may need intensive weight loss regimens to prevent MS development.