Background: This meta-analysis was performed to investigate the relationship between methylation of the P14 and O6-methylguanine-DNA methyltransferase (MGMT) genes and the risk of hepatocellular carcinoma (HCC). Materials and Methods: We searched PubMed, EMBASE, the Chinese Biomedical Database (CBM), and the China National Knowledge Infrastructure (CNKI) databases to identify relevant studies that analysed HCC tissues for P14 and MGMT gene methylation status; we then performed a meta-analysis. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to evaluate the association between gene methylation and the risk of HCC. Results: Ten studies that assessed P14 gene methylation in 630 HCC tumour tissues and nine studies analysing MGMT methylation in 497 HCC tumour tissues met our inclusion criteria. Our meta-analysis revealed that the rate of P14 methylation was significantly higher in HCCs than in adjacent tissues (OR 3.69, 95%CI 1.63-8.35, p=0.002), but there was no significant difference in MGMT methylation between HCC and adjacent tissues (OR 1.76, 95%CI 0.55-5.64, p=0.34). A subgroup analysis according to ethnicity revealed that P14 methylation was closely related to the risk of HCC in Chinese and Western individuals (Chinese, OR 7.74, 95%CI 1.36-44.04, p=0.021; Western, OR 3.60, 95%CI 1.49-8.69, p=0.004). Furthermore, MGMT methylation was not correlated with the risk of HCC in Chinese individuals (OR 2.42, 95%CI 0.76-7.73, p=0.134). The combined rate of P14 methylation was 35% (95%CI 24-48%) in HCC tumour tissues and 11% (95%CI 4-27%) in adjacent tissues, whereas the combined rate of MGMT methylation was 15% (95%CI 6-32%) in HCC and 10% (95%CI 4-22%) in adjacent tissues. Conclusions: These results suggest that the risk of HCC is related to P14 methylation, but not MGMT methylation. Therefore, P14 gene methylation may be a potential biomarker for the diagnosis of HCC.