Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths and ranks as the fifth most common cancer. Detecting HCC early is crucial for improving patient outcomes. In this study, we evaluated the diagnostic potential of Fibroblast Growth Factor 19 (FGF-19) and Voltage-gated Calcium Channel α2δ1 subunit (VGCC α2δ1) in HCC. Patients and methods: In this prospective study, serum FGF-19 and VGCC α2δ1 levels were compared among 44 HCC patients, 26 patients with cirrhosis but without HCC, and 15 healthy controls. Receiver operating characteri-stic curve (ROC) analysis was used to evaluate the diagnostic potential of FGF-19 and VGCC α2δ1 in HCC, as well as their complementary role with AFP. The study also investigated the correlation between these levels and clinicopathological characteristics. Results: Serum FGF-19 levels were signi-ficantly higher in HCC patients compared to patients with cirrhosis and healthy controls. Additionally, FGF-19 levels were significantly elevated in cirrhotic patients compared to healthy controls. VGCC α2δ1 levels were significantly higher in both HCC and cirrhotic patients compared to healthy controls, with no significant difference between the HCC and cirrhosis groups. The diagnostic performance of FGF-19 was superior to that of VGCC α2δ1 in HCC diagnosis, with FGF-19 demonstrating 95.5% sensitivity, 76.9% speci-ficity, and 88.5% accuracy, while VGCC α2δ1 showed 25% sensitivity, 100% specificity, and 53% accuracy. A strong positive correlation was found between FGF-19 and VGCC α2δ1 with AFP. The combination of VGCC α2δ1, FGF-19, and AFP resulted in a sensitivity of 21%, specificity of 100%, and accuracy of 63%, which did not show superior diagnostic performance compared to FGF-19 alone. Conclusion: FGF-19 is an excellent positive and a good negative test. VGCC α2δ1 is very poor positive and good negative test. Their com-bined use with AFP may improve the diagnostic efficiency of HCC.