Background Hepatocellular carcinoma (HCC) is the most common primary liver tumor and represents the third-leading cause of cancer-related death in the world. The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, with the majority of cases caused by chronic infection with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and initiation of antiviral therapy appears to reduce the incidence of HCC in patients with chronic HBV or HCV infection. Additionally, the use of ultrasonography enables the early detection of small liver tumors and forms the backbone of recommended surveillance programs for patients at high risk for the development of HCC. Cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, represent further noninvasive techniques that are increasingly employed to diagnose HCC in patients with cirrhosis. The mainstay of potentially curative therapy includes surgery – either resection or liver transplantation. However, most patients are ineligible for surgery, because of either advanced disease or underlying liver dysfunction, and are managed with locoregional and/or systemic therapies. Randomized controlled trials have demonstrated a survival benefit with both local therapies, either ablation or embolization, and systemic therapy in the form of the multikinase inhibitor sorafenib. Despite this, median survival remains poor and recurrence rates significant. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the diagnosis and treatment of this highly lethal cancer. Objectives Evaluation of Serum voltage gated calcium channel α2δ1 as a novel Marker for diagnosis of Hepatocellular Carcinoma in Cirrhotic Egyptian Patients. Patients and Methods This study had been carried out on 90 subjects, age range 21-73 year selected from Internal medicine and Hepatology outpatient clinics and inpatient wards at Ain shams university hospitals. Subjects were divided as follow: Group A(Case): 40 patients with liver cirrhosis without Hepatocellular carcinoma and group B (Control): 40 patients with liver cirrhosis and Hepatocellular carcinoma and group C: 10 normal population for detecting normal value of the marker with exclusion criteria including age < 18 years old and Patients diagnosed with malignancy other than HCC. Results The study subjects are classified into three groups: Group A cirrhotic patients without HCC, Group B cirrhotic patients with HCC and Group C normal individual subjects. Conclusion Serum voltage gated calcium channel levels were significantly higher in patients with HCC and mildly elevated in patients with liver cirrhosis compared to the control group. Thus it can be used as a tumor marker for HCC.