We investigated the relationship of polymorphisms in the cholecystokinin 1 receptor [CCK1R; G to T (n-128), A to G (n-81)] and the beta3-adrenergic receptor (beta3-AR; Trp64Arg) with midlife weight gain. The participants were 1012 Japanese men and women (40 to 59 years of age). Their weight at 18 years old was obtained from a questionnaire. Weight change was defined as the current weight minus the weight at 18 years old. Subjects were grouped into four categories by these genotypes: W/W=noncarriers, W/H=Arg64 carriers of the beta3-AR, H/W=T (n-128) or G (n-81) carriers of the CCK1R, H/H=T (n-128) or G (n-81) and Arg64 carriers. In men, the interaction between the CCK1R and beta3-AR polymorphisms was significant (two-way ANOVA, p < 0.05), but neither the CCK1R nor the beta3-AR was individually associated with weight gain. The H/H group showed a higher possibility of weight gain of 10 kg or more compared with the W/W group in men. The odds ratio for weight gain (> or =10 kg) of H/H was 2.54 (95% confidence interval: 1.50 to 4.30) compared with W/W. In women, neither main effect nor interaction was significant. These results suggest that the combination of CCK1R and the beta3-AR polymorphisms is a contributing factor for midlife weight gain in men.