Purpose: In order to find a novel non-invasive bio-marker with high accuracy for the diagnosis of hepatocellular carcinoma (HCC), we examined the predictive power of AEG-1 as a potential bio-marker in HCC. Methods: A total of 184 serum samples (117 samples from HCC patients, 67 samples from healthy volunteers) were collected. We measured the levels of AEG-1 with reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR) in all specimens. X-2 analysis was used to explore the correlation between the expression levels of AEG-1 and clinicopathological parameters. In addition, receiver operating characteristic (ROC) curve analyses was performed to reveal whether the serum AEG-1 could be promising diagnostic bio-marker for HCC. Results: The expression of AEG-1 mRNA was significantly higher in HCC patients than healthy volunteers (P<0.05). AEG-1 expression level was related with tumor size, tumor number, AJCC stage, T classification, N classification, M classification, histological differentiation, vascular invasion, distant metastasis and serum AFP levels (P<0.05), but had no relation with age and gender. ROC curve demonstrated that the optimal cutoff point was 0.733. Besides, the area under ROC curve (AUC) was 0.85, suggesting AEG-1 could act as a diagnostic marker for HCC (P=0.000, 95% CI=0.791-0.908). Conclusion: Taken together, AEG-1 mRNA was positively expressed in HCC serum compared to the healthy controls. AEG-1 could be a novel serum bio-marker for HCC.