Cdc6 play crucial roles in DNA replication and carcinogenesis. The biological significance of the Cdc6 G1321A polymorphism (V441I, rs13706) is still not elucidated. Here we examined the influence of this polymorphism on the function of Cdc6 and the individual's susceptibility to non-Hodgkin lymphoma (NHL) and hepatocellular carcinoma (HCC). Unconditional logistic regression analysis revealed that the risk for NHL was significantly reduced in both AG heterozygotes [odds ratio (OR)=0.67, P=0.019] and AA homozygotes (OR=0.54, P=0.026), compared with GG homozygotes. Further stratification by subtypes of NHL showed that the AG as well as combined AA/AG genotypes were associated with decreased risk for B-cell-NHL (OR=0.62, P=0.011 and OR=0.61, P=0.006, respectively), especially for diffuse large B-cell lymphoma (DLBCL, OR=0.63, P=0.025 and OR=0.62, P=0.012, respectively). In addition, male individuals with the AA genotype displayed borderline significantly reduced risk for HCC (OR=0.48, P=0.054). Interestingly, the G1321A polymorphism did not affect caspase-mediated cleavage of Cdc6 during etoposide-induced apoptosis, but it was predicted to alter the secondary structure of Cdc6 mRNA. Our data provide the first evidence that the Cdc6 G1321A polymorphism is associated with decreased risk of cancer. Further studies are necessary to confirm the general validity of our findings.