Several lines of evidence have implicated that neurotrophins play an important role in the pathophysiology of mood disorders. This study examined whether a common missense polymorphism (S205L) of a gene encoding the p75NTR, the low-affinity receptor for neurotrophins, is associated with depressive disorder in a Japanese sample of 164 patients and the same number of controls matched for age and sex. There were significant differences in the genotype distribution and allele frequency between the cases and controls. The minor allele (L205) was significantly decreased in the patients than in the controls (P < 0.05, odds ratio 0.54, 95% CI 0.31–0.94), suggesting that this allele may have a protective effect against the development of major depression. Furthermore, this association was more strongly observed in the patients with a history of attempted suicide than those without such a history. Our results suggest that the S205L polymorphism of the p75NTR gene is involved in the pathogenesis of depressive disorder and suicidal behavior. © 2004 Wiley-Liss, Inc.