Abstract: Objective To investigate the expression of G protein-coupled receptor 124 (GPR124) in hepatocellular carcinoma (HCC) tissues, and to explore its relationship with HCC progression and prognosis. Methods qRT-PCR and Western blot analysis were used to detect GPR124 mRNA and protein expression respectively in 15 paired HCC and adjacent normal liver tissues. Immunohistochemical analysis was used to detect GPR124 expression in 64 cases formalin-fixed, paraffin-embedded HCC tissues with complete followup data. Results The levels of GPR124 mRNA and protein expression in HCC were significantly higher than those in adjacent liver tissues (P<0.05). GPR124 expression in paraffin-embedded HCC tissues were significantly higher than those in adjacent liver tissues (P<0.05). GPR124 expression were positively related with tumor size, tumor number, TNM stage and microvascular invasion (P<0.05). HCC patients with higher GPR124 expression had lower overall survival and disease free survival(P<0.05). Conclusion GPR124 overexpression has a significant correlation with the progression and prognosis of HCC, and it would provide a wonderful probability for predicting prognosis and designing new targeted drugs.