Methyl-CpG binding domain 2 (MBD2) leads to the silencing of methylated genes in cancer cells and was implicated in the activation of prometastatic genes in hepatocellular carcinoma (HCC). The present study aimed to investigate the expression status of MBD2 in HCC and the correlation with surgical outcomes. The correlation between clinical prognostic factors and MBD2 were also evaluated. MBD2 expression was analyzed by western blotting in 20 paired HCC and paratumor liver (PTL) tissues. In addition, immunohistochemistry was performed on the 159 HCC samples following hepatic resection performed between January 2003 and October 2008. The correlation between clinicopathological factors and MBD2 expression was also evaluated by statistical analysis to determine the prognostic value of MBD2 expression in HCC. Postoperative prognostic factors were evaluated using univariate and multivariate analyses. Compared with PTL tissues, MBD2 expression was shown to be upregulated in 10 of the 20 HCC tissues (50%) by western blotting. The immunohistochemistry data indicated significant increase of the MBD2 expression level in 81 cases (50.94%) compared with the PTL tissues (0/159, 0%, P<0.001). The upregulated MBD2 expression in HCC tissues was correlated with BCLC stage B, tumor size >5 cm and microscopic vascular invasion. Multivariate analysis revealed that MBD2 was an independent prognostic factor for overall survival [HR, 2.089; P=0.001] and disease-free survival (HR, 1.601; P=0.022). In conclusion, MBD2 expression was elevated in HCC tissue, which suggesting MBD2 as a candidate prognostic marker of HCC.