Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer-related deaths worldwide. Early diagnosis of HCC remains a great challenge in clinic. Novel and effective biomarkers are in urgent need in early diagnosis of HCC.Serum levels of neurotrophin-receptor-interacting melanoma antigen-encoding gene homolog (NRAGE) were measured for 107 patients with HCC, 98 patients with benign liver diseases, and 89 healthy controls using quantitative real-time polymerase chain reaction. Receiver operating characteristic curve was applied to evaluate the diagnostic capacity of serum NRAGE in HCC.NRAGE expression was significantly higher in patients with HCC than in controls (all, P < .05). Moreover, its expression was tightly correlated with TNM stage (P = .004). NRAGE could distinguish patients with HCC from healthy controls with the area under the curve (AUC) of 0.874, yielding a sensitivity of 81.3% and a specificity of 78.7%. Additionally, in differentiation between benign liver diseases and HCC, the AUC value of NRAGE was 0.726, with a sensitivity of 63.6% and a specificity of 73.5%. Meanwhile, alpha-fetoprotein also could distinguish patients with HCC from benign liver disease cases, with an AUC of 0.677, a sensitivity of 64.4%, and a specificity of 60.2%.NRAGE could be a potential biomarker for HCC early diagnosis.