Background: Hepatocellular carcinoma (HCC) is a primary hepatic malignant tumor and represents about 82.5% of primary liver cancers. Lactoferrin level has been demonstrated to increase in both microbial infection and inflammation. As a result, an increased lactoferrin level could provide a talented biomarker for gastrointestinal (GI) disease. Objective: To evaluate the value of ascitic fluid lactoferrin (AFLAC) in diagnosis of HCC in cases with cirrhotic ascites. Patients and Methods: This case control study included 120 patients divided into two groups (Group A: 60 patients with cirrhotic ascites without HCC) and (Group B: 60 patients with cirrhotic ascites + HCC). Every participant was subjected to abdominal ultrasonography, triphasic CT abdomen, ascitic fluid analysis and assessment of AFLAC. Results: AFLAC level was statistically significantly higher in HCC group compared to non-HCC group. There was statistically significant higher ascitic fluid lactate dehydrogenase (LDH) in HCC group than in non-HCC group. In HCC group, there was a statistically significant positive correlation between AFLAC and ascitic fluid (AF) protein and ascitic fluid LDH. AFLAC could be used as an excellent predictor in differentiation between HCC and non-HCC groups. Conclusion: Increased AFLAC level in cirrhotic patients with HCC seems to be a talented diagnostic indicator, even following receiving systemic antibiotic therapy. HCC development is detected by accident in advanced stages in the majority of the cases when therapeutic measures cannot be provided, so rapid detection of high-risk cases by AFLAC could help to offer early and efficient management.