Objective:The present study aims to investigate the association of unipolar depression (UPD) with six serotonergic gene polymorphisms in Han Chinese.Methods:One hundred and thirty-two UPD patients and 180 healthy controls were genotyped for polymorphisms of six serotonergic genes, including tryptophan hydroxylase (TPH1 A218C), serotonin transporter promoter region (5-HTTLPR), serotonin receptor 2A (5-HT2AR −1438G/A), serotonin receptor 2C (5-HT2CR Cys23Ser), serotonin receptor 6 (5-HT6R C267T) and serotonin receptor 1Dβ (5-HT1DβR T371G). Symptomatic clusters were evaluated by the 24-item Hamilton Rating Scale for Depression (HAMD).Results:The frequencies of S/S genotype and S allele in 5-HTTLPR polymorphism were significantly higher in UPD patients than in healthy controls. There was a significant difference in distributions of genotypes in 5-HT2CR Cys23Ser polymorphism between UPD patients and control subjects, but the difference became no significant when the data were further stratified by gender. The patients with genotypes G/G and T/G of 5-HT1DβR T371G polymorphism had significantly lower scores of diurnal variation evaluated by HAMD than those with genotype T/T, while the patients with genotype T/G had significantly higher scores of hopelessness than those with genotypes G/G and T/T. There were no significant differences in genotypic and allelic distributions of TPH1 A218C, 5-HT2AR −1438G/A or 5-HT6R C267T polymorphisms between the case and control groups.Conclusion:The study demonstrates that 5-HTTLPR and 5-HT2CR Cys23Ser polymorphisms might contribute to susceptibility of UPD, and the genotype T/T in 5-HT1DβR T371G polymorphism might be a risk factor for diurnal variation, while T/G might be a protective factor against hopelessness in Han Chinese populations.