Chronic hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) are common liver diseases that lead to death in Egypt, especially in men. The current study aimed to evaluate the diagnostic sensitivity of arginase (ARG) activity, alpha-1 antitrypsin (AAT), and alpha-fetoprotein (AFP) in the sera of patients with HCV (with & without viremia) and HCC. A total of 190 men classified as 40 healthy used as control (G1), 100 infected with HCV (subdivided into 50 with viremia (G2) and 50 without viremia (G3), and 50 with HCC (G4). The activity of ARG significantly decreased in HCV and HCC groups along with significant elevation in the level of AAT and AFP as compared with the control. Although a non-significant variation was scored in AST/ALT, significant differences were observed among AST/ARG and ARG/ALT in the pathogenic groups as compared with the healthy group. Moreover, significant variations in ARG, AAT, AFP, AST/ARG, and ARG/ALT were observed between viremia and non-viremia. Although AFP scored significant change among the viremia and HCC, the rest parameters scored non-significant changes between both groups. Furthermore, a receiver operating characteristic curve (ROC) showed the diagnostic ability for the selected parameters with high sensitivity and multiple linear regressions exhibited good associations between those parameters. These findings suggest the using possibility of ARG, AAT, and AFP in the diagnosis and/or follow-up of patients with HCV or HCC.