Controversies surrounding the effectiveness of fiber intake for prevention of obesity can be attributed to differences in the genetic makeup of individuals. This study aims to examining the interaction between dietary fiber intake and common fat mass and obesity-associated (FTO) single-nucleotide polymorphisms (SNPs), in relation to obesity. Subjects of this nested case-control study were selected from among adult participants of the Tehran Lipid and Glucose Study. Cases (n = 627) were individually matched with controls, who had normal weight. Six selected SNPs (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973, and rs3751812) were genotyped by tetra-refractory mutation system-polymerase chain reaction analysis. Genetic risk scores (GRS) were calculated using the weighted method. A significant interaction was observed between total fiber intake and the GRS in relation to obesity (Pinteraction = 0.01); the difference in the risk for obesity was more pronounced in individuals with GRS ≥ 6 who consumed ≥ 14 grams of fiber a day (OR: 2.74, CI: 2.40-3.35 vs Ref.; P trend = 0.0005) than in individuals with GRS < 6 (P trend = 0.34). Dietary fiber intakes modified the association of FTO SNPs and the GRS with general obesity, an effect which was more pronounced in those who consumed high levels of dietary fiber and had a high number of risk alleles.