To examine the association between the risk of obesity and the Trp64Arg polymorphism of the beta(3)-adrenergic receptor gene.A case-control study was conducted. The case series encompassed 159 subjects with a body mass index >30 kg/m(2) (obesity) and no other major diseases except for type 2 diabetes, and the controls were 154 healthy subjects with a body mass index <25 kg/m(2). 313 Spanish subjects between 20 and 60 years of age were screened for the Trp64Arg mutation.The prevalence of the Trp64Arg mutation was similar among cases (19.5%) and control subjects (16.2%). The association between the risk of obesity and the Trp64Arg mutation was estimated using multivariate logistic regression. A higher odds ratio of 3.84 (95% CI 1.33-11.12) for the mutation was found among younger individuals (20-35 years), while no increased risk was apparent among older participants (35-60 years). Moreover, when the model was adjusted for gender, age, and leisure-time physical activity, the product-term for interaction (effect modification) between age and the presence of the Trp64Arg mutation was statistically significant (likelihood ratio test p = 0.035).Individuals aged 20-35 years who are Trp64Arg carriers had a substantially higher risk of developing obesity, independent of their sex or leisure-time physical activity.