Substantial evidence supports a role for dysfunction of the serotonin transporter (5-HTT) in the pathogenesis of major depression. The polymorphism of the serotonin transporter gene (5-HTTLPR) was found to be associated with reduced hippocampal volume in major depression. However, the original diallelic polymorphism was criticized, because the L-allele can be subtyped into La and Lg alleles, the latter of which is thought to be similar to the S-allele. Therefore, the study aim was to examine the influences of the triallelic (La-Lg-S system) and diallelic 5-HTTLPR on hippocampal volumes in patients with major depression and healthy controls. Using high-resolution MRI hippocampal volumes and polymorphisms (5-HTTLPR) were measured in 60 in-patients with major depression and 60 healthy controls. Patients with the La/La genotype had significantly smaller hippocampal gray and white matter than La/La controls. No significant differences were found between patients and controls with La/(Lg + S) or (Lg + S)/(Lg + S) genotype. Moreover, within the patient group the La/La homozygous genotype had significantly smaller hippocampal white matter volumes than the La/(Lg + S) or (Lg + S)/(Lg + S) genotype. In conclusion, with the diallelic as well as the triallelic system the homozygosity for the long-allele is associated with decreased hippocampal volumes in patients with major depression, but not in healthy controls, suggesting that disease or stress specific processes linked to the serotonergic system may enhance the vulnerability to morphological alterations.