Background: Hepatocellular carcinoma (HCC) is the world's sixth most common cancer, and it usually complicates liver cirrhosis. Its prevalence is growing globally, with annual increases ranging from 3% to 9%. Despite the fact that the alpha fetoprotein (AFP) is the gold standard for HCC serodiagnosis, it has a high rate of false positive outcomes, which are associated with a bad diagnosis. Objective: To investigate the potential role of chromogranin-A (CgA) as a diagnostic non-invasive marker for HCC and to assess its sensitivity and specificity in diagnosis of HCC compared to AFP. Material and Methods: This study was conducted from October 2017 till March 2020 at the Department of Tropical Medicine, Ain Shams University and Theodor Bilharz research institute. The study included 35 patients diagnosed with hepatocellular carcinoma HCC and 35 patients with chronic liver diseases (CLD). The study also included 20 apparently healthy individual served as a healthy control group taken from the blood donors at the blood bank of Ain Shams University Hospital. AFP and CgA serum levels were detected for all groups using enzyme linked immunosorbent assay (ELISA). Results: The results of the study showed that the median of the of CgA in the HCC group was 53.40 and in CLD group was 22.55 while in the control group was 15.30; which indicates a significant elevation of CgA in HCC patients. Conclusion: CgA is one of the promising tumor markers in hepatic focal lesions for detection of HCC.