BACKGROUND:Injection drug use (IDU) is associated with multiple health harms. The vast majority of IDU initiation events (in which injection-naïve persons first adopt IDU) are assisted by a person who injects drugs (PWID), and as such, IDU could be considered as a dynamic behavioral transmission process. Data suggest that opioid agonist treatment (OAT) enrollment is associated with a reduced likelihood of assisting with IDU initiation. We assessed the association between recent OAT enrollment and assisting IDU initiation across several North American settings and used dynamic modeling to project the potential population-level impact of OAT scale-up within the PWID population on IDU initiation. METHODS AND FINDINGS:We employed data from a prospective multicohort study of PWID in 3 settings (Vancouver, Canada [n = 1,737]; San Diego, United States [n = 346]; and Tijuana, Mexico [n = 532]) from 2014 to 2017. Site-specific modified Poisson regression models were constructed to assess the association between recent (past 6 month) OAT enrollment and history of ever having assisted an IDU initiation with recently assisting IDU initiation. Findings were then pooled using linear mixed-effects techniques. A dynamic transmission model of IDU among the general population was developed, stratified by known factors associated with assisting IDU initiation and relevant drug use behaviors. The model was parameterized to a generic North American setting (approximately 1% PWID) and used to estimate the impact of increasing OAT coverage among PWID from baseline (approximately 21%) to 40%, 50%, and 60% on annual IDU initiation incidence and corresponding PWID population size across a decade. From Vancouver, San Diego, and Tijuana, respectively, 4.5%, 5.2%, and 4.3% of participants reported recently assisting an IDU initiation, and 49.4%, 19.7%, and 2.1% reported recent enrollment in OAT. Recent OAT enrollment was significantly associated with a 45% lower likelihood of providing recent IDU initiation assistance among PWID (relative risk [RR] 0.55 [95% CI 0.36-0.84], p = 0.006) compared to those not recently on OAT. Our dynamic model predicts a baseline mean of 1,067 (2.5%-97.5% interval [95% I 490-2,082]) annual IDU initiations per 1,000,000 individuals, of which 886 (95% I 406-1,750) are assisted by PWID. Based on our observed statistical associations, our dynamic model predicts that increasing OAT coverage from approximately 21% to 40%, 50%, or 60% among PWID could reduce annual IDU initiations by 11.5% (95% I 2.4-21.7), 17.3% (95% I 5.6-29.4), and 22.8% (95% I 8.1-36.8) and reduce the PWID population size by 5.4% (95% I 0.1-12.0), 8.2% (95% I 2.2-16.9), and 10.9% (95% I 3.2-21.8) relative to baseline, respectively, in a decade. Less impact occurs when the protective effect of OAT is diminished, when a greater proportion of IDU initiations are unassisted by PWID, and when average IDU career length is longer. The study's main limitations are uncertainty in the causal pathway between OAT enrollment and assisting with IDU initiation and the use of a simplified model of IDU initiation. CONCLUSIONS:In addition to its known benefits on preventing HIV, hepatitis C virus (HCV), and overdose among PWID, our modeling suggests that OAT scale-up may also reduce the number of IDU initiations and PWID population size.