Polymorphisms in the promoter region (5-HTTLPR) of the serotonin transporter and a variable number of tandem repeats polymorphism in the second intron have been widely studied. However, the results of association studies examining unipolar depression (MDD) or bipolar disorder depression (BPD) have been mixed. To precisely ascertain small associations with both polymorphisms, a meta-analysis was performed involving several thousand subjects, using random-effects modeling. For MDD, the effect of the 5-HTTLPR genotype was significant (chi2=6.1, P<0.05), with 21% of MDD subjects and 17% of controls homozygous for the short (S) allele (odds ratio, 1.16). Similar findings were noted in BPD, with a higher frequency of S/S genotypes in affected patients, although the results did not reach statistical significance. Results of transmission disequilibrium tests trended in a similar direction but also did not reach statistical significance. No consistent effect of the variable number of tandem repeats polymorphism was revealed for either MDD or BPD. The results suggest that the S allele, or a neighboring allele in linkage disequilibrium, is recessive for MDD and possibly BPD. Notably, the association is very small. With these small associations, confounding issues such as population stratification require addressing. Significant heterogeneity between studies was also evident, possibly reflecting differences in diagnosis, different control populations, and different ethnic populations. These factors should Influence the interpretation of the association found in this analysis.