Objective: To investigate the expression of reticulocalbin-1 (RCN1) in cancer tissues of patients with hepatocellular carcinoma and its clinical significance. Methods: The clinical data of 95 patients with hepatocellular carcinoma admitted to our hospital from January 2012 to January 2014 were reviewed. The expression of RCN1 in hepatocellular carcinoma pathological specimens was detected by immunohistochemistry. According to the results of immunohistochemistry, the patients were divided into two groups, RCN1 high and low expression group. The Kaplan-Meier curve method and the log-rank test were used to compare the difference between the tumor-free survival rate and the overall survival rate of patients with high and low RCN1 expression. The Cox proportional hazard model was used to analyze the risk factors for tumor-free survival and overall survival in hepatocellular carcinoma. Results: Of the 95 patients with HCC, 61 (64.2%) had high RCN1 expression and 34 (35.8%) had low RCN1 expression. RCN1 expression was significantly associated with gender (P=0.031), alpha-fetoprotein (AFP) (P<0.001), tumor Size (P=0.032), number of tumor nodules (P=0.028), tumor thrombus (P=0.011), and degree of differentiation (P=0.001). Tumor-free survival (P=0.001) and overall survival rate of high RCN1 expression group (P<0.001) was significantly lower than that of patients with low RCN1 expression group. Multivariate analysis showed that RCN1 expression (P=0.01) was an independent prognostic factor predicting tumor-free survival in HCC patients. Analysis showed that RCN1 expression (P<0.01) and TNM staging (P=0.02) were independent prognostic factors predicting overall survival in patients with HCC. Conclusion: The tumor-free survival rate and overall survival rate of patients with high RCC expression in HCC are significantly lower than those with low RCN1 expression, which is a molecular marker for predicting the prognosis of HCC.