Abstract  The purpose of the present study was to determine if a 5‐HT6 receptor polymorphism is associated with antidepressant treatment response in major depressive disorder (MDD). Ninety‐one patients with MDD, compared with 127 normal control subjects, were evaluated after an 8‐week treatment period. An association analysis revealed no differences in genotype and allele distribution between patients with MDD and normal control subjects. However, there were significant differences in the treatment response in some Hamilton Depression Rating Scale (HAM‐D) scores (sleep, activity, somatic anxiety, and total) between genotypes. Moreover, the heterozygote group (CT genotype) had significantly better treatment response than the homozygote group (CC + TT genotypes), especially in the somatic‐anxiety subcategory and the total score of HAM‐D. These findings imply that a 5‐HT6 receptor polymorphism (C267T) is associated with treatment response in MDD.