BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Viral hepatitis, alcoholism and non-alcoholic steatohepatitis are the most common risk factors. Despite the advances in HCC screening and treatment options, HCC still has a high mortality rate and a high rate of recurrence after treatment. Lipocalin-2 (LCN-2) is a glycoprotein transporter that is highly expressed in HCC tissues. OBJECTIVE: To evaluate serum LCN-2 as a diagnostic marker for HCC. METHODS: The study was carried out in Zagazig university hospitals. It included 210 HCC patients (subdivided in three subgroups), 72 liver cirrhosis patients without HCC and 18 normal control persons (the total is 300 subjects). All the study subjects were evaluated by history taking, physical examination, routine laboratory investigations, alpha-fetoprotein (AFP) and LCN-2 in addition radiology. RESULTS: In comparison between HCC and control, there was a statistically significant difference in hemoglobin percent (HB%), platelet count, serum ALT, AST, ALP, bilirubin, albumin and creatinine. In comparison to AFP, LCN-2 > 225 ng/ml had a higher diagnostic performance in HCC patients and was more accurate in differentiation between cirrhosis and HCC patients. CONCLUSION: LCN-2 is a good candidate for HCC diagnosis and screening