Hepatocellular carcinoma (HCC) is usually asymptomatic in the early stage and does not show elevated alpha-feto protein (AFP). Des-Gamma-CarboxyProthrombin (DCP) and Carbohydrate antigen 19-9 (CA19-9) may increase in sera of HCC patients. The ultimate goal is to evaluate the potential role of DCP and CA19-9 compared to AFP as early diagnostic, non-invasive markers for chronic hepatitis C patients with and without HCC. 26 chronic HCV patients, 26 HCC related to HCV and 25 normal controls were studied. Quantitative determination of AFP, DCP and CA19-9 concentrations in sera was done using commercially available Enzyme-linked Immunosorbent Assay (ELISA) kits. Results: In HCC patients, AFP showed the highest diagnostic accuracy (90.2%) followed by DCP (80.4%) and CA19-9 (70.6%). AFP showed the highest specificity and sensitivity (100%-80.8%). DCP and CA19-9 showed the same specificity (92%) but DCP showed higher sensitivity (69.2%) than CA19-9 (50%). In HCV patients, CA19-9 showed the highest diagnostic accuracy (74.5%) followed by DCP (70.6%). AFP showed the lowest diagnostic accuracy (58.8%).Both CA19-9 and DCP showed highest specificity (100%), AFP is the lowest (84%). CA19-9 showed the highest sensitivity (50%), followed by DCP (42.3%) and AFP (34.6%). Significant higher levels of DCP and CA-19-9 were detected in HCC patients with low AFP levels (P<0.05).Conclusion: Serum levels of DCP and CA19-9 could be used as sensitive tumor markers to detect HCV patients with HCC and also to detect HCV patients who are at risk to develop cancer.