Objective To evaluate the abnormal methylation of p14, p15, p16, and RB in the cancerous tissues of liver cancer patients and to investigate the significance of detection of multigene methylation for the early diagnosis of liver cancer. Methods Methylation-specific PCR was used to evaluate the methylation status of p14, p15, p16, and RB in the cancerous tissues of 44 liver cancer cases and the cirrhotic tissues of 41 liver cirrhosis cases as well as the paracancerous tissues of the 44 liver cancer cases. The obtained data were subjected to chi-square test and Fisher′s exact test. Results Among the 41 liver cirrhosis cases, the methylation of p14, p15, p16, and RB was detected in 7 cases (17.1%), 11 cases (28.9%), 15 cases (36.6%), and 3 cases (7.3%), respectively. Among the 44 liver cancer cases, the methylation of p14, p15, p16, and RB was detected in 15 cases (34.1%), 25 cases (56.8%), 31 cases (70.5%), and 12 cases (273%), respectively. In the 44 paracancerous tissues, p16 methylation was detected in 4 cases, and p15 methylation in 1 case. The methylation rates of the four genes were significantly higher in liver cancer tissues and liver cirrhosis tissues than in paracancerous tissues (P<0.05). There were no significant differences in the methylation rates of the four genes among liver cancer patients with different ages, sexes, degrees of tumor differentiation, and clinical stages (P>0.05). Conclusion The methylation of p14, p15, p16, and RB is frequent in the pathogenesis of liver cancer. The detection of multigene methylation is of certain significance for early diagnosis of liver cancer.