INTRODUCTION: Reduced brain serotonin (5-HT) function is believed to increase the risk for eating-related disturbances. Differences in 5-HT vulnerability are genetically determined, including a short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) that is associated with serotonin dysfunction and is therefore believed to increase the risk for obesity. However, considerable variability has been apparent to replicate these findings. OBJECTIVE: Because reduced control of energy intake often results from distress and negative mood (emotional eating) and because brain 5-HT controls stress adaptation and mood changes, the aim of the current study was to investigate whether the S-allele may particularly contribute toward weight gain in cognitive stress-vulnerable individuals with high neuroticism. METHODS: A total of 857 healthy young male and female college students (21.0+/-2.1 years; BMI 19-25 kg/m) were genotyped for the 5-HTTLPR polymorphism S'/S' (S/S, S/LG, LG/LG), S'/L' (S/La, La/Lg) and L'/L' (LA/LA) and trait neuroticism. The interaction of 5-HTTLPR by neuroticism was assessed on BMI. RESULTS: BMI increased significantly as a function of the presence of the S-allele of 5-HTTLPR only in high neurotic individuals. CONCLUSION: These results indicate that cognitive stress vulnerabilities are critical mediators of the association between 5-HTTLPR and body weight.