Depression and Genetic variation in serotonin and monoamine transmission have both been associated with body mass index (BMI), but their interaction effects are not well understood. We examined the interaction between depressive symptoms and functional polymorphisms of serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) on categories of BMI. Participants were from the National Longitudinal Study of Adolescent Health. Multiple logistic regression was used to investigate interactions between candidate genes and depression on risk of obesity (BMI > or = 30) or overweight + obese combined (BMI > or = 25). Males with an MAOA active allele with high depressive symptoms were at decreased risk of obesity (OR 0.22; 95% CI 0.06-0.78) and overweight + obesity (OR 0.48; 95% CI 0.26-0.89). No similar effect was observed among females. These findings highlight that the obesity-depression relationship may vary as a function of gender and genetic polymorphism, and suggest the need for further study.