Altered neurotrophin functions have been implicated in major depressive disorder (MDD). Previously, we reported an association between MDD and a missense polymorphism (Ser205Leu: rs2072446) of the gene encoding the p75 neurotrophin receptor (p75(NTR)). However, contradictive negative results have also been reported. This study tried to replicate the association in an independent sample. Subjects were 668 patients with MDD and 1130 healthy controls. The proportion of individuals carrying the Leu205 allele was significantly decreased in the patients than in the controls (χ(2)=5.3, d.f.=1, P=0.021, odds ratio (OR) 0.74, 95% confidential interval (CI) 0.58-0.96). When allele frequencies were compared, the Leu205 allele was significantly reduced in the patients than in the controls (χ(2)=4.4, d.f.=1, P=0.037, OR 0.78, 95% CI 0.61-0.99). When men and women were examined separately, there was a significant difference in genotype and allele distributions in women (genotype: χ(2)=8.3, d.f.=1, P=0.0039, OR 0.60, 95% CI 0.43-0.85; allele: χ(2)=7.3, d.f.=1, P=0.0069, OR 0.64, 95% CI 0.47-0.89), but not in men. The present study provided support for the previously reported association between the Ser205Leu polymorphism of the p75(NTR) gene and MDD, indicating that the Leu205 allele has a protective effect against the development of MDD, particularly in women.