Tryptophan hydroxylase-1 (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, and selective serotonin reuptake inhibitors (SSRIs) exert their activity enhancing the general serotonergic tone. Citalopram is the most selective SSRI, with little or no affinity for a variety of receptor types. The goal of this study was to investigate whether the A218C polymorphism of the TPH1 gene is associated with the citalopram antidepressant response in subjects with major depressive disorder (MDD). All of the patients were evaluated using the 21-item Hamilton Depression Rating Scale before beginning and after 8 weeks of citalopram treatment. Genotyping was performed with the polymerase chain reaction. The remission rate to citalopram treatment was worse in MDD subjects with the TPH1 A/A and A/C genotypes than in those with the TPH1 C/C genotype. Our results suggest that the A218C polymorphism of the TPH1 gene serves as a modulator of antidepressant activity, especially in terms of treatment remission.