Injecting drug use is the main risk of hepatitis C virus (HCV) transmission in most developed countries. HCV antiviral treatment (peginterferon-α + ribavirin) has been shown to be cost-effective for patients with no reinfection risk. We examined the cost-effectiveness of providing antiviral treatment for injecting drug users (IDUs) as compared with treating ex/non-IDUs or no treatment. A dynamic model of HCV transmission and disease progression was developed, incorporating: a fixed number of antiviral treatments allocated at the mild HCV stage over 10 years, no retreatment after treatment failure, potential reinfection, and three baseline IDU HCV chronic prevalence scenarios (20%, 40%, and 60%). We performed a probabilistic cost-utility analysis estimating long-term costs and outcomes measured in quality adjusted life years (QALYs) and calculating the incremental cost-effectiveness ratio (ICER) comparing treating IDUs, ex/non-IDUs, or no treatment. Antiviral treatment for IDUs is the most cost-effective option in the 20% and 40% baseline chronic prevalence settings, with ICERs compared with no treatment of £521 and £2,539 per QALY saved, respectively. Treatment of ex/non-IDUs is dominated in these scenarios. At 60% baseline prevalence, treating ex/non-IDUs is slightly more likely to be the more cost-effective option (with an ICER compared with no treatment of £6,803), and treating IDUs dominated due to high reinfection. A sensitivity analysis indicates these rankings hold even when IDU sustained viral response rates as compared with ex/non-IDUs are halved. Conclusion: Despite the possibility of reinfection, the model suggests providing antiviral treatment to IDUs is the most cost-effective policy option in chronic prevalence scenarios less than 60%. Further research on how HCV treatment for injectors can be scaled up and its impact on prevalence is warranted. (HEPATOLOGY 2012)