We have previously shown that the Egyptian Hepatitis C Virus Risk Score (EGCRISC), an Egyptian hepatitis C virus (HCV) risk-based screening tool, to be valid and cost-effective. Certain behaviours, occupations and diseases have been shown to be associated with an increased risk of exposure to HCV infection and constitute a major population reservoir of HCV infection. This study investigated the efficacy of EGCRISC in selected high-risk groups by testing 863 participants from four groups: slaughterhouse workers, illicit drug users (IDUs), female sex workers and human immune deficiency virus (HIV) patients. Data for this study were collected on EGCRISC and another pre-designed risk factor questionnaire. Sera were tested for HCV antibodies by ELISA. EGCRISC, at lower cut-off points, showed significantly good performance (P < 0.05) in all four groups except for females <45 years, but was reliable in detecting HCV cases (sensitivity: 84.21% and negative predictive value: 94.5%). Specific scores for IDUs and HIV patients were developed that showed high accuracy (P < 0.001). A modified EGCRISC for high-risk groups (EGCRISC-HRGs) was shown to be a valid tool that is recommended for use in high-risk populations if no other specific screening tool is available or universal screening is applied. EGCRISC for IDUs (EGCRISC-IDUs) and EGCRISC for HIV patients (EGCRISC-HIV) are useful tools for preselecting potentially HCV-infected cases for further testing in settings where serological analysis is not readily available or accessible.