Hepatitis C virus (HCV) is one of the leading causes of chronic liver disease worldwide. The fundamental feature of disease progression is increasing degrees of fibrosis, ending in cirrhosis which may be complicated by Hepatocellular Carcinoma (HCC). Apoptosis plays a critical role in adult tissue homeostasis. Caspase recruitment domains (CARD) are protein modules found in many proteins that regulate apoptosis with more than 20 human CARD-containing proteins have been identified and many of them were implicated in various carcinogenesis processes. In this study, we investigated the possible relation of CARD9, CARD10 and COP in progression of liver fibrosis and pathogenesis of HCC in chronic HCV patients. A total number of 130 patients were recruited and classified into 4 groups: Group I; included 30 patients with chronic HCV and persistent normal liver profile with F0 or F1 fibrosis stage by liver biopsy, Group II; included 30 patients with elevated liver enzymes and no cirrhosis in liver biopsy, Group III; included 30 patients with cirrhosis in liver biopsy in addition to Group IV which included 40 patients with HCC. The expression levels of mRNA of CARD9, CARD10 and COP were quantitatively estimated by reverse transcription-polymerase chain reaction analysis in all liver biopsy specimens and it was significantly higher in HCC group when compared with all other groups. We concluded that CARD9, CARD10 and COP may be involved in hepatic carcinogenesis process and hence it could be used as a marker for prediction of HCC. Nevertheless, further studies with a larger sample size are mandatory to underline the accuracy of our findings before their application at the population level.