HCV reinfection following successful treatment can compromise treatment outcomes. This systematic review assessed the rate of HCV reinfection following treatment among people with recent drug use and those receiving opioid agonist therapy (OAT). We searched bibliographic databases and conference abstracts for studies assessing post-treatment HCV reinfection rates among people with recent drug use (injecting or non-injecting) or those receiving OAT. Meta-analysis was used to cumulate reinfection rates and meta-regression was used to explore heterogeneity across studies. Thirty-six studies were included (6,311 person-years of follow-up). The overall rate of HCV reinfection was 5.9/100 person-years (95% CI 4.1–8.5) among people with recent drug use (injecting or non-injecting), 6.2/100 person-years (95% CI 4.3–9.0) among people recently injecting drugs, and 3.8/100 person-years (95% CI 2.5–5.8) among those receiving OAT. Reinfection rates were comparable following interferon-based (5.4/100 person-years; 95% CI 3.1–9.5) and direct-acting antiviral (3.9/100 person-years; 95% CI 2.5–5.9) therapy. In stratified analysis, reinfection rates were 1.4/100 person-years (95% CI 0.8–2.6) among people receiving OAT with no recent drug use, 5.9/100 person-years (95% CI 4.0–8.6) among people receiving OAT with recent drug use, and 6.6/100 person-years (95% CI 3.4–12.7) among people with recent drug use not receiving OAT. In meta-regression analysis, longer follow-up was associated with lower reinfection rate (adjusted rate ratio aRR per year increase in mean/median follow-up 0.77; 95% CI 0.69–0.86). Compared with people receiving OAT with no recent drug use, those with recent drug use receiving OAT (aRR 3.50; 95% CI 1.62–7.53), and those with recent drug use not receiving OAT (aRR 3.96; 95% CI 1.82–8.59) had higher reinfection rates. HCV reinfection risk following treatment was higher among people with recent drug use and lower among those receiving OAT. The lower rates of reinfection observed in studies with longer follow-up suggested higher reinfection risk early post-treatment. Our findings demonstrate that although reinfection by hepatitis C virus occurs following successful treatment in people with recent drug use, the rate of hepatitis C reinfection is lower than the rates of primary infection reported in the literature for this population – reinfection should not be used as a reason to withhold therapy from people with ongoing injecting drug use. The rate of hepatitis C reinfection was lowest among people receiving opioid agonist therapy with no recent drug use. These data illustrate that harm reduction services are required to reduce the reinfection risk, while regular post-treatment hepatitis C assessment is required for early detection and retreatment. Display omitted •We assessed the rate of HCV reinfection after treatment among people who recently used drugs and those receiving opioid agonist therapy.•The rate of reinfection was lowest among people receiving opioid agonist therapy with no recent drug use.•The rate of HCV reinfection was comparable after interferon therapy or direct-acting antiviral therapy.•A higher rate of HCV reinfection was observed in studies with shorter follow-up.