The CpG island hypermethylation of the suppressor of cytokine signaling-1 (SOCS-1) gene is frequently methylated in hepatocellular carcinoma (HCC), but its clinicopathological significance and the potential risk factors for the epigenetic change in HCC remain poorly understood. The methylation status of SOCS-1 CpG island was evaluated in fresh-frozen tissues from 284 HCC patients using the methylation-specific polymerase chain reaction. The expression of SOCS-1 protein was analyzed by immunohistochemical staining. SOCS-1 methylation was found in 163 (57%) of 284 HCCs. SOCS-1 methylation was positively associated with patient age (P=0.002) and HCV infection status (P=0.004), and was inversely associated with HBV infection (P=0.0002). In the multivariate logistic regression analysis, the HB(s)Ag-negative HCCs showed a 2.78 (95% CI=1.31-5.89, P=0.007) times greater risk of SOCS-1 methylation than the HB(s)Ag-positive HCCs. SOCS-1 methylation also occurred at a 4.34 times (95% CI=1.24-14.25, P=0.02) higher prevalence in antiHCV-positive cases than in antiHCV-negative cases. No prognostic effect of SOCS-1 methylation was observed in the HCCs. In conclusion, the present study suggests that SOCS-1 methylation in HCC may be negatively associated with HB(s)Ag status.