It is not till it is discovered that high individual incomes will not purchase the mass of mankind immunity from cholera, typhus, and ignorance, still less secure them the positive advantages of educational opportunity and economic security, that slowly and reluctantly, amid prophecies of moral degeneration and economic disaster, society begins to make collective provision for the needs which no ordinary individual, even if he works overtime all his life, can provide himself.-R.H. Tawney, Equality (1931)

IMPORTANCE The United States is experiencing a crisis of opioid overdose. In response, the US Department of Health and Human Services has defined a goal to reduce overdose mortality by 40% by 2022. OBJECTIVE To identify specific combinations of 3 interventions (initiating more people to medications for opioid use disorder [MOUD], increasing 6-month retention with MOUD, and increasing naloxone distribution) associated with at least a 40% reduction in opioid overdose in simulated populations. DESIGN, SETTING, AND PARTICIPANTS This decision analytical model used a dynamic populationlevel state-transition model to project outcomes over a 2-year horizon. Each intervention scenario was compared with the counterfactual of no intervention in simulated urban and rural communities in Massachusetts. Simulation modeling was used to determine the associations of community-level interventions with opioid overdose rates. The 3 examined interventions were initiation of more people to MOUD, increasing individuals' retention with MOUD, and increasing distribution of naloxone. Data were analyzed from July to November 2020. MAIN OUTCOMES AND MEASURES Reduction in overdose mortality, medication treatment capacity needs, and naloxone needs. RESULTS No single intervention was associated with a 40% reduction in overdose mortality in the simulated communities. Reaching this goal required use of MOUD and naloxone. Achieving a 40% reduction required that 10% to 15% of the estimated OUD population not already receiving MOUD initiate MOUD every month, with 45% to 60%% retention for at least 6 months, and increased naloxone distribution. In all feasible settings and scenarios, attaining a 40% reduction in overdose mortality required that in every month, at least 10% of the population with OUD who were not currently receiving treatment initiate an MOUD. CONCLUSIONS AND RELEVANCE In this modeling study, only communities with increased capacity for treating with MOUD and increased MOUD retention experienced a 40% decrease in overdose mortality. These findings could provide a framework for developing community-level interventions to reduce opioid overdose death.