The present study investigated whether dietary patterns could interact with fat mass and obesity-associated (FTO) polymorphisms in relation to changes in BMI and waist circumference (WC) over 3⋅6 years of follow-up. Subjects were selected from participants of the Tehran Lipid and Glucose Study (n 4292, 43⋅2 % male). Dietary data were collected using a valid and reliable FFQ. Dietary patterns were determined using factor analysis. The genotypes of polymorphisms (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973 and rs3751812) were determined. Genetic risk score (GRS) was calculated using the weighted method. Mean ages of men and women were 42·6 (sd 14) and 40⋅4 (sd 13) years, respectively. The healthy (e.g. vegetables and fruits) and the Western dietary patterns (WDP; e.g. soft drinks and fast foods) were extracted. In carriers of the risk alleles rs1121980, rs1421085, rs8050136, rs1781799 and rs3751812, BMI was approximately 2-fold higher in individuals in the higher quartile of WDP score, compared with the first quartile (P < 0⋅05). WC increased with increasing WDP score in carriers of the risk alleles rs1121980 and rs3751812, but not in individuals who did not carry any risk alleles. BMI and WC increased to a greater extent in the high GRS group while increasing quartiles of the WDP score, compared with the low GRS group (BMI change; Q1: 1⋅04 (se 0⋅34) v. Q4: 2⋅26 (se 0⋅36)) (WC change; Q1: 0⋅47 (se 0⋅32) v. Q4: 0⋅95 (se 0⋅34)) (Pinteraction < 0⋅05). These results suggest that adults with higher genetic predisposition to obesity are more susceptible to the harmful effects of adherence to the WDP, which emphasised the need to reduce the consumption of unhealthy foods for the prevention of obesity.