Objective To investigate the serum level of high mobility group box-1(HMGB-1) in patients with liver cancer and its correlation with p53 and clinical pathological features of liver cancer. Methods Serum levels of HMGB-1 and p53 were determined by ELISA in 20 patients with hepatocellular carcinoma, 20 with cholangiocellular carcinoma and 20 healthy volunteers. Results Serum HMGB-1 levels in hepatocellular carcinoma patients ([83.8±17.4] ng/ml) and cholangiocellular carcinoma patients ([95.9±21.4] ng/ml) were significantly higher than that in the healthy volunteers ([8.4±2.6] ng/ml, P<0.05). Serum p53 levels in hepatocellular carcinoma patients ([251.0±45.6] pg/ml) and cholangiocellular carcinoma patients ([267.8±47.4] pg/ml) were also significantly higher than that in the healthy volunteers ([160.0±28.4] pg/ml, P<0.05). Serum HMGB-1 level was positively correlated with the serum p53 level in the hepatocellular carcinoma patients (r=0.660 3, P<0.05) and cholangiocellular carcinoma patients (r=0.614 2, P<0.05). Serum HMGB-1 and p53 levels were not correlated with the age, gender, tumor size, or number of tumors (P>0.05), but were correlated with the TNM stage, differentiation degree and metastasis status (P<0.05).Conclusion Serum HMGB-1 level is positively correlated with p53, and both HMGB-1 and P53 influence the pathogenesis of liver cancer.