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Background Direct-acting antiviral (DAA) therapy is highly effective in people who inject drugs (PWID); however, rates, specific injection behaviors, and social determinants associated with hepatitis C virus (HCV) reinfection following DAA therapy among PWID on opioid agonist therapy (OAT) are poorly understood. Methods PREVAIL was a randomized controlled trial that assessed models of HCV care for 150 PWID on OAT. Those who achieved sustained virologic response (SVR) (n = 141; 94%) were eligible for this extension study. Interviews and assessments of recurrent HCV viremia occurred at 6-month intervals for up to 24 months following PREVAIL. We used survival analysis to analyze variables associated with time to reinfection. Results Of 141 who achieved SVR, 114 had a least 1 visit in the extension study (62% male; mean age, 52 years). Injection drug use (IDU) was reported by 19% (n = 22) in the extension study. HCV reinfection was observed in 3 participants. Over 246 person-years of follow-up, the incidence of reinfection was 1.22/100 person-years (95% CI, 0.25–3.57). All reinfections occurred among participants reporting ongoing IDU. The incidence of reinfection in participants reporting ongoing IDU (41 person-years of follow-up) was 7.4/100 person-years (95% CI, 1.5–21.6). Reinfection was associated with reporting ongoing IDU in the follow-up period (P <.001), a lack confidence in the ability to avoid contracting HCV (P <.001), homelessness (P =.002), and living with a PWID (P =.007). Conclusions HCV reinfection was low overall, but more common among people with ongoing IDU following DAA therapy on OAT, as well as those who were not confident in the ability to avoid contracting HCV, homeless, or living with a PWID. Interventions to mediate these risk factors following HCV therapy are warranted. [ABSTRACT FROM AUTHOR]