RATIONALE: Polymorphisms of the serotonin transporter gene (5-HTTLPR) may be associated with increased vulnerability to acute tryptophan depletion (ATD) and depression vulnerability especially following stressful life events. OBJECTIVE: The aim of the present study was to investigate the effects of ATD in subjects with different 5-HTTLPR profiles before and after stress exposure on affective and cognitive-attentional changes. MATERIALS AND METHODS: Eighteen subjects with homozygotic short alleles (S'/S') and 17 subjects with homozygotic long alleles (L'/L') of the 5-HTTLPR participated in a double-blind, placebo-controlled, crossover design to measure the effects of ATD on mood, memory, and attention before and after acute stress exposure. RESULTS: ATD lowered mood in all subjects independent of genotype. In S'/S' genotypes, mild acute stress increased depressive mood and in L'/L' genotypes increased feelings of vigor. Furthermore, S'/S' genotypes differed from L'/L' genotypes on measures of attention independent of treatment and memory following ATD. CONCLUSIONS: Polymorphisms of the 5-HTTLPR differentially affect responses to mild stress and ATD, suggesting greater vulnerability of S'/S' carriers to serotonergic manipulations and supporting increased depression vulnerability.