Background Direct acting antiviral agents (DAAs) altered hepatitis C virus (HCV) outcomes with a permanent cure in 90% of cases. However, HCV had not wiped out from all cases (1% ~ 15%), which represent occult HCV infection (OCI). Aim of the work Detecting prevalence and predictors of OCI in four high-risk groups. Patients and methods 196 participants were enrolled and assigned into four patients groups and one control group; group I (cryptogenic hepatitis), group II (HCV), group III (chronic HBV), group IV (ESRD), and group V (control group). HCV RNA testing in serum and in peripheral blood mononuclear cells, hepatic stiffness estimation and FIB-4 score calculation were done for all participants. Results Significant differences were found among different study groups regarding frequencies of HTN (p<0.001) and DM (p<0.001), history of blood transfusion (p<0.001), history of previous surgery (p<0.001), as well as mean values of FIB-4 (p<0.001) and fibroscan readings (p=0.002). OCI was found in 25 participants (12.7%), with different prevalence rates in different groups; being highest in group I (11/43, 25.3%),followed by group III (6/30, 20%).Among all participants, OCI was significantly associated multiple risk factors that include; history of blood transfusion (p=0.004), previous surgery (p=0.017), positive family history of HCV infection (p<0.001), advanced fibrosis (p =0.015) and high FIB-4 score (p=0.016). Positive family history of HCV infection and history of blood transfusion were considered as independent predictors for OCI. Conclusion Testing for OCI in high-risk populations and retesting in SVR cases might be needed to help in complete eradication of chronic HCV infection.