AIM: To investigate the expression of Neurensin-2 ( NRSN2) in hepatocellular carcinoma (HCC) and its prognostic values in predicting survival. METHODS: The expression and prognostic significance of NRSN2 in HCC was examined by performing immunohistochemical analysis using a total of 110 HCC clinical tissue samples, and Western blotting analysis to further confirm the result. RESULTS: Decreased NRSN2 expression was shown in 70.9% cases. Loss of NRSN2 expression in HCC was significantly related to tumor size ( P = 0.006). Larger tumor size was related to negative expression of NRSN2. Patients showing negative NRSN2 expression had a significantly shorter overall survival than those with positive expression ( P = 0.008). Multivariate Cox regression analysis indicated that NRSN2 expression level was an independent factor of survival ( P = 0.013). Western blotting analysis further confirmed decreased expression of NRSN2 in tumor tissues compared with non-tumorous tissues. CONCLUSION: Our study indicated that NRSN2 could be a tumor suppressor gene for HCC and a candidate biomarker for long-term survival in HCC.