BACKGROUND: According to the humor theory of Traditional Uighur Medicine (TUM), a same disease is classified into different abnormal humor types and corresponding methods are applied to treat the diseases according to the type of abnormal humor characteristics. To date the biological foundation of classification of diseases by humor theory has been little studied and the mechanism of action is still unclear. In the present study, we aimed to investigate the association between some related gene polymorphisms and depression with abnormal humor in TUM. METHODS: 201 cases of depression patients in a Uighur population were divided into two groups as: 107 cases of depression patients with abnormal black bile (ABB), 94 cases of depression patients with none abnormal black bile (nABB), and 50 healthy people were served as control group. Venous blood was used to isolate DNA samples, and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used for genotyping of single nucleotide polymorphisms (SNPs). Polymorphisms in the serotonin 2A (5-HT2A) receptor gene, brain derived neurotrophic factor (BDNF), serotonin 1A (5-HT1A) receptor gene were investigated in each groups, respectively. RESULTS: The 5-HT2A A-1438G, 5-HT2A T102C, BDNF Val66Met, and 5-HT1A C-1019G gene polymorphisms showed significant association with ABB. However, no difference between nABB and controls was found for those genotype distribution and allele frequency. Moreover, the T102C and A1438G SNPs in the 5-HT2A receptor gene polymorphisms were in linkage disequilibrium. In addition, the OR associated with the combination of Val66Met-Val/Val genotype plus the presence of -1019C allele was 8.393 for ABB compared with controls (OR 8.393; 95% CI 1.807 ~ 38.991; P = 0.003). Moreover, the OR associated with the presence of -Met plus -1019C alleles was 12.194 for ABB compared with controls (OR 12.194; 95% CI 1.433 ~ 103.776; P = 0.005). The OR associated with the presence of -1438C/C plus Val/Val genotypes was 7.738 for ABB compared with controls (OR 7.738; 95% CI 1.566 ~ 38.241; P = 0.005). CONCLUSION: It was concluded that there were significant relationship between the gene polymorphisms and classification of depression with abnormal humor in TUM. The 5-HT2A A-1438G, 5-HT2A T102C, BDNF Val66Met, and 5-HT1A C-1019G gene polymorphisms might predict the incidence of depression with ABB.