The JWA gene was initially cloned as a novel cell differentiation-associated gene and was subsequently found to be an environmental responsive gene. The JWA gene also produced a marked effect during chemical-induced multidirectional differentiations of primary and human myeloid leukemia cells. Recently, a novel single nucleotide polymorphism (SNP) in exon2 of the JWA gene (454CA) was identified that may play a role in risk of bladder cancer. The aim of this study was to investigate the association between the 454CA (NM_006407.2) in JWA exon2 variants and risk of leukemia in a hospital-based case-control study of 202 leukemia patients and 289 cancer-free controls. Results indicated that 454A allele was found to associate with significantly increased risk of leukemia, although the 454CA is a synonymous polymorphism in coding region of the JWA gene. In conclusion, the potentially functional genetic polymorphism 454CA of the JWA gene appears to contribute to the risk of multiple kinds of leukemia in a south Chinese population.