Background: Hepatoma is the most common primary hepatic malignant tumor, and it frequently occurs in people who have had cirrhosis. There is a continuous need to utilize an early, accurate, and non-invasive biomarker for hepatocellular carcinoma (HCC) diagnosis. The most prevalent miRNA in the adult human liver is microRNA 122 (miR-122), primarily expressed in hepatocytes. Cytokeratin-18 (CK18) is a cytoskeleton component that belongs to the cytokeratin superfamily. Both have been suggested as diagnostic biomarkers for many malignant diseases. Aim of the study: To clarify the significance of measuring serum CK18 levels and miR-122 as diagnostic markers for HCC in cirrhotic patients. Patients and methods: Fifty patients diagnosed with HCC and fifty patients with HCV-induced liver cirrhosis were included in our study. A detailed history was obtained from the cases, followed by a complete clinical examination. Laboratory investigations were done for all the cases, including the measurement of alpha-fetoprotein. Analysis of cytokeratin-18 was done by ELISA (DRG International Inc, USA) and Mir-122 by real-time PCR. Results: There was a statistically significant elevation in the three biomarkers (AFP, miRNA, and CK18) in the HCC group versus the cirrhotic group. The sensitivity of miRNA and CK18 was higher in the detection of HCC as compared with AFP (96%, 100%, and 62%, respectively). However, the specificity of miRNA was lower as compared with AFP. Conclusion: CK18 and miR-122 could be utilized as good diagnostic tools for identifying HCC in cirrhotic patients with higher diagnostic ability than AFP.