Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease and exposure to dietary toxins such as aflatoxins and aristolochic acid. Objective: To determine the value of serum Medkine level as a potential biomarker for patients with hepatocellular carcinoma. Patients and methods: This study was conducted at the Gastroenterology and Hepatology Unit, Department of Internal Medicine Al-Azhar and Misr University for Science and Technology. 90 Egyptian patients were recruited and were divided into 3 Group I included 30 patients with liver cirrhosis, HCC was excluded in these patients at time of recruitment in the study, exclusion of HCC was based on the absence of any hepatic focal lesion in abdominal ultrasonography scanning. Group II included 40 patients with HCC. Diagnosis of HCC was based on the appearance of typical vascular pattern of enhancement in triphasic spiral CT scan of the abdomen. Control Group included 20 age and sex-matched apparently healthy subjects. Results: Different liver function tests showed no statistically difference between two groups except for ALK. Ph and gamma glutamyltransferase (GGT) which were significant higher in group II than group I. There was a highly statistically significance difference regarding alpha-fetoprotein (AFP) which was higher in group II than group I and control group. Serum AFP levels were found to be significantly correlated with larger tumor size in this study. In addition, patients with advanced-stage hepatocellular carcinomas had significantly higher median AFP serum levels (BCLC B/C) than that of early-stage tumors (BCLC 0/A) (237ng/mL versus 23ng/mL). However, no significant correlation was found between serum midkine (MDK) levels with tumor size, number or serum levels of AFP, and no significant association was found between serum MDK levels and BCLC stages. The best cutoff values for MDK and AFP to discriminate HCC cases from those with liver cirrhosis were 0.39 and 10ng/mL, respectively, with sensitivities (90% versus 77.5%), specificities (60% versus 80%). The overall diagnostic performance of MDK for HCC diagnosis was much better than that of AFP. On comparing the sensitivities and specificities of MDK at the cutoff 0.39ng/mL to those of AFP at different cutoff values (10 and 400), the overall diagnostic performance of MDK for HCC diagnosis was much better than that of AFP. Conclusion: Alpha-fetoprotein and midkine may have a complementary role in hepatocellular carcinoma surveillance and screening. Midkine increased the diagnostic yield in alpha-fetoprotein -negative hepatocellular carcinoma and the presence of either elevated alpha-fetoprotein or midkine increased the sensitivity of hepatocellular carcinoma detection. Midkine was also superior to alpha-fetoprotein in the diagnosis of NASH-related hepatocellular carcinoma and this finding postulated an exciting novel role for midkine in NASH-related carcinogenesis.