Abstract Background and study aim : The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. We aimed to evaluate the performances of serum alpha -1-acid glycoprotein (AAG) for the diagnosis of HCC, especially for HCC with low alpha-fetoprotein (AFP). Patients and methods: Nighty patients included in this study, 60 had HCC, and 30 (50%) of these were AFP low HCC (AFP ≤ 20 ng/mL). The remaining 30 patients were chronic hepatitis C and cirrhosis without HCC as control group. Plasma AAG was analyzed using quantitative enzyme immunoassay technique. Results: Serum level of AAG was significantly elevated in low AFP HCC group compared with high AFP HCC and cirrhotic without HCC group, 1307.20 ±9627 vs (850.82±795.14 and 309.77±220.17 respectively). Reciever operating characteristic (ROC) curve showed that the best cut off for AAG and AFP was 740 μg/ml and 20 ng/mL respectively. The area under the curve of AAG was significantly higher than that for AFP (0.95 vs 0.92) respectively. AAG at a cut-off value of 740 μg/ml provides higher sensitivity (73.3% vs 62%, respectively) and specificity (74.0%, and 71%, respectively) in low AFP HCC than high AFP HCC . Conclusion: The role of AFP in the diagnosis of HCC is limited, AAG had better performance in diagnosing HCC patients with low AFP. So Serum level of AAG might be used as a potential diagnostic marker for hepatocellular carcinoma.