Objective: Checkpoint kinase 2 gene (CHEK2) is an important mediator of the DNA damage response pathway. Single nucleotide polymorphisms (SNPs) have been shown to influence the developing risk and clinical characteristics in various types of human malignancies. The values of CHEK2 SNPs in HBV-related hepatocellular carcinoma patients (HCC) were unknown and discussed here. Methods: The expression and prognostic prediction role of CHEK2 were searched and analyzed in HBV-related HCC patients by GEO database. SNPs in CHEK2 were genotyped by SNP selection tools, and further assessed their associations with clinical outcomes of 339 HBV-related HCC patients. Results: Patients with a higher CHEK2 gene expression predicted a worse relapse free survival (RFS). Moreover, those with a variant alleles CC/TT of SNPs rs1547014 and rs738722 had a significantly better prognosis when compared to the patients with CT genotype (P<0.015 for rs1547014, P=0.001 for rs738722), and CC/TT genotype combined with AFP <= 400 ng/ml also predicted the best prognosis in HBV-related HCC patients. In stratified analysis, the protective effect of rs1547014 and rs738722 CC/TT genotype was more evident in patients with adverse strata, comparing the patients with favorable strata. Conclusion: CHEK2 SNPs rs1547014 and rs738722 probably be potential prognostic bio-markers in HBV-related HCC patients.