A functional polymorphism in the promoter region of the 5-hydroxytryptamine (serotonin) transporter (5-HTT) gene, termed 5-HTTLPR, alters transcription of the 5-HTT gene. The short variation (S allele) produces less transcriptional efficiency of serotonin, which can partly account for psychiatric disorders. Despite strong biological plausibility, the relationship between 5-HTTLPR and the risk of major depressive disorder (MDD) is unclear. To elucidate the relationship, we applied meta-analysis techniques to molecular studies of 5-HTTLPR and MDD.A total of 22 articles were identified from MEDLINE through March 2008, using the search keywords 'depression,' '5-HTTLPR', and 'polymorphism.' The authors assessed the evidence of genotypic association using STATA Version 8.2.Summary frequencies of the S allele of 5-HTTLPR among Caucasians and Asians based on the random effects model were 42.1% [95% confidence interval (CI) = 40.5-43.6] and 76.8% (95% CI = 73.9-79.7), respectively. The distribution of the S allele was significantly different between Asians and Caucasians (P<0.001). The SS genotype was significantly associated with an increased risk of MDD among Caucasian populations (odds ratio = 1.41, 95% CI = 1.15-1.72), although there was no significant association among Asians.Although the summary risk for developing MDD in individuals with the 'at-risk' SS genotype of 5-HTTLPR may be small, MDD is such a common disease that even a small increase in risk translates to a large number of excess MDD cases in the population. Thus, 5-HTT may be a candidate MDD susceptibility gene.