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Introduction Accumulating evidences indicate that circadian abnormalities lead to sleep disorder, neurodegenerative diseases and depression. We have reported that the polymorphisms of a clock-related gene, Tef, contributed to the risk of sleep disturbances and depression in Parkinson disease. The objective of the present study was to examine whether the three clock genes we previous studied are associated with major depressive disorder (MDD) in the Chinese population. Methods 105 subjects with MDD and 485 control subjects participated in this case-control study. Demographics, Mini-mental Status Examination (MMSE), and Hamilton rating scale for depression (HAMD) were obtained in all subjects. Genotypes of SNPs (single nucleotide polymorphism) of Cry1 rs2287161, Cry2 rs10838524 and Tef rs738499 was screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results MDD cases had a significantly higher frequency carrying the C allele and CC genotype in Cry1 rs2287161 and the T allele and TT genotype in Tef rs738499 than controls. Limitations The sample size of MDD group was relatively small. Conclusions The polymorphisms of Cry1 rs2287161 and Tef rs738499 are associated to MDD.