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Background: Chronic hepatitis C virus (HCV) infection affects 58 million people globally. The frequency of HCV infection in the general Iranian population is less than 0.5%; however, a concentrated epidemic was reported among people who use drugs, particularly those with a history of drug injection. Objectives: This cross-sectional study was performed to assess the prevalence of HCV infection among high-risk groups outside of prison in northeastern Iran. Methods: A total of 962 participants in Razavi Khorasan province were enrolled from 2018 to 2022. They included drug users referred to drug treatment and harm reduction centers and individuals with a history of crimes such as drug use or imprisonment who worked in a private industrial unit. Serum anti-HCV antibodies were assessed using a rapid or ELISA kit, and seroreactive samples were confirmed by single-step reverse transcriptase or qualitative real-time polymerase chain reactions. A P-value < 0.05 was considered statistically significant. Results: The mean age of 707 males and 255 females was 39.8 ± 10.2 years. Anti-HCV antibodies were detected from 129 samples (13.41%), of which 107 were available for polymerase chain reaction testing. HCV RNA was detected in 88 cases (75.2%); the total viremia rate was calculated as 9.26% (88/950). Logistic regression analysis revealed that HCV infection among drug users was significantly associated with older age (P = 0.002), being single (P = 0.009), and history of drug injection (P < 0.001) or incarceration (P = 0.04). Conclusions: The findings showed a considerably high prevalence of HCV infection among people who use drugs in northeastern Iran. To achieve the global goal of viral hepatitis elimination by 2030, we strongly recommend stricter screening and treatment of this infection among such hard-to-access populations in Iran. [ABSTRACT FROM AUTHOR]