The activation of Na+/H+ exchanger 1 (NHE1) is involved in the formation of tumor cell pseudopodia, possibly resulting in their malignant potential. The clinicopathological significance of NHE1, however, is not yet well known in the case of hepatocellular carcinoma (HCC). In this study, we first analyzed the NHE1 expression in 100 cases of hepatocellular carcinoma (HCC) and found that NHE1, at both messenger RNA and protein levels, was over-expressed in majority of HCC tissues compared with matched non-cancerous tissue. In addition, the increased expression of NHE1 correlated with tumor size, venous invasion and advanced pTNM stage (P<0.05). Kaplan-Meier curves demonstrated that patients with increased NHE1 expression were at significantly increased risk for shortened survival time (P<0.05). This is the first demonstration that the expression level of NHE1 is correlated with tumor progression and prognosis in HCC. We proposed that NHE1 may have diagnostic and therapeutic potential for patients with HCC.