OBJECTIVE : Serotonin, or 5-hydroxytryptamine (5-HT), and serotonin receptor (HTR) subtypes contribute to controlling energy homeostasis. We investigated the association of polymorphisms of serotonin related genes with type 2 diabetes in Korean adults using a community-based prospective cohort study. METHODS : A total of 8840 participants (4205 Ansung, 4635 Ansan) from the Korean Genome and Epidemiology Study (KoGES)-Ansan and Ansung were included. The mean follow-up duration was 7.6 years, and the Ansan and Ansung cohorts were treated as independent replicates. Individuals with existing and new-onset type 2 diabetes were identified at baseline and follow-up evaluations, respectively. Logistic regression analysis was used to evaluate the association of 3402 single nucleotide polymorphisms (SNPs) in serotonin related genes with type 2 diabetes after adjusting for baseline age, sex, body mass index, drinking status, and smoking status. RESULTS : The baseline case-control comparison revealed significant association of 26 SNPs in HTR3B and HTR2A with type 2 diabetes. Interestingly, HTR3B SNP rs1176744, which is involved in behavioral disorders, was associated with type 2 diabetes (p-value = 0.0002). Furthermore, HTR3B polymorphisms that significantly associated with type 2 diabetes were located in the 3' downstream region. The new-onset type 2 diabetes case-control study revealed significant association of 3 additional SNPs of the HTR4. CONCLUSIONS : We found that rs1176744 in HTR3B was associated with type 2 diabetes. Additionally, our study suggests that polymorphisms in the downstream region of HTR3B may contribute to the development of type 2 diabetes.