OBJECTIVE: To investigate a kallikrein-related peptidase 2 (KLK2) single nucleotide polymorphism (SNP) in relation to male infertility because of its role in semen processing. We investigated the genetic association of the KLK2+255G>A genotype with male infertility. METHODS: We genotyped the SNP site located in intron 1 (+255G>A, rs2664155) of KLK2 from 218 men with male infertility (cases) and 220 fertile males (controls). Pyrosequencing analysis was performed for the genotyping. RESULTS: The SNP of the KLK2 gene had a statistically significant association with male infertility (p<0.05). The odds ratio for the minor allele (+255A) in the pooled sample was 0.47 (95% confidence intervals, 0.26-0.85) for rs2664155. CONCLUSION: The relationship of KLK2 SNP to male infertility is statistically significant, especially within the non-azoospermia group. Further study is needed to understand the mechanisms associated with male infertility.