Objective : Ubiquitin-specific peptidase 46 gene (USP46) polymorphisms is part of ubiquitin-proteasome system, which is responsible for dynamic cellular processes such as the regulation of cell cycle. USP46 has been reported to be associated with major depressive disorder. The objective of the present study was to investigate the association of USP46 polymorphisms with affective temperamental traits in healthy subjects. Methods : A total of 557 Korean healthy volunteers were recruited, and 545 subjects (328 male, 217 female) were included in the final analysis. The DNA of the subjects was isolated from saliva samples. Two single-nucleotide polymorphisms (SNPs) rs346005, rs2244291 in USP46 were genotyped. Affective temperaments were assessed using the Korean version of Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A). Results : A significant association was found between rs346005 genotypes and TEMPS-A only in male subjects. In particular, subjects with the CC genotype of rs346005 showed a more depressive temperament than subjects with AA or CA genotypes in males. For rs2244291, there were no associations between the rs2244291 genotypes and TEMPS-A scores. Conclusion : Some affective temperaments may serve as a genetic predisposing factors for affective disorders, such as depressive disorder, via vulnerability genes related to the ubiquitin-proteasome system.