Background: The total population health benefits and costs of HIV preexposure prophylaxis (PrEP) for people who inject drugs (PWID) in the United States are unclear.

Objective: To evaluate the cost-effectiveness and optimal delivery conditions of PrEP for PWID.

Design: Empirically calibrated dynamic compartmental model.

Data Sources: Published literature and expert opinion.

Target Population: Adult U.S. PWID.

Time Horizon: 20 years and lifetime.

Intervention: PrEP alone, PrEP with frequent screening (PrEP+screen), and PrEP+screen with enhanced provision of antiretroviral therapy (ART) for individuals who become infected (PrEP+screen+ART). All scenarios are considered at 25% coverage.

Outcome Measures: Infections averted, deaths averted, change in HIV prevalence, discounted costs (in 2015 U.S. dollars), discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.

Results of Base-Case Analysis: PrEP+screen+ART dominates other strategies, averting 26 700 infections and reducing HIV prevalence among PWID by 14% compared with the status quo. Achieving these benefits costs $253 000 per QALY gained. At current drug prices, total expenditures for PrEP+screen+ART could be as high as $44 billion over 20 years.

Results of Sensitivity Analysis: Cost-effectiveness of the intervention is linear in the annual cost of PrEP and is dependent on PrEP drug adherence, individual transmission risks, and community HIV prevalence. Limitation: Data on risk stratification and achievable PrEP efficacy levels for U.S. PWID are limited.

Conclusion: PrEP with frequent screening and prompt treatment for those who become infected can reduce HIV burden among PWID and provide health benefits for the entire U.S. population, but, at current drug prices, it remains an expensive intervention both in absolute terms and in cost per QALY gained.