Variation in genes implicated in serotonin neurotransmission may interact with environmental factors to influence antidepressant response. We aimed to determine how a range of polymorphisms in serotonergic genes determine this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. In total, 14 single nucleotide polymorphisms (SNPs) in coding regions of 10 serotonergic genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR3A, HTR3C, HTR3D, HTR3E, HTR5A and TPH2) were genotyped in 308 Chinese Han patients with major depressive disorder. Response to 6 weeks' antidepressant treatment was determined by change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score, and previous stressful events were evaluated by the Life Events Scale (LES) and Childhood Trauma Questionnaire-Short Form (CTQ-SF). Two 5-HT1B receptor SNPs (rs6296 and rs6298) and one tryptophan hydroxylase2 (rs7305115) SNP were significantly associated with antidepressant response in this Chinese sample, as was a haplotype in TPH2 (rs7305115 and rs4290270). A gene-gene interaction on antidepressant response was found between SNPs in HTR1B, HTR3A and HTR5A in female subjects. The HTR1B SNPs demonstrated interaction with recent stress, while that for TPH2 interacted with childhood trauma to influence antidepressant response.