ImportanceIn 2021, the state of Rhode Island distributed 10 000 additional naloxone kits compared with the prior year through partnerships with community-based organizations.ObjectiveTo compare various strategies to increase naloxone distribution through community-based programs in Rhode Island to identify one most effective and efficient strategy in preventing opioid overdose deaths (OODs).Design, Setting, and ParticipantsIn this decision analytical model study conducted from January 2016 to December 2022, a spatial microsimulation model with an integrated decision tree was developed and calibrated to compare the outcomes of alternative strategies for distributing 10 000 additional naloxone kits annually among all individuals at risk for opioid overdose in Rhode Island.InterventionsDistribution of 10 000 additional naloxone kits annually, focusing on people who inject drugs, people who use illicit opioids and stimulants, individuals at various levels of risk for opioid overdose, or people who misuse prescription opioids vs no additional kits (status quo). Two expanded distribution implementation approaches were considered: one consistent with the current spatial distribution patterns for each distribution program type (supply-based approach) and one consistent with the current spatial distribution of individuals in each of the risk groups, assuming that programs could direct the additional kits to new geographic areas if required (demand-based approach).Main Outcomes and MeasuresWitnessed OODs, cost per OOD averted (efficiency), geospatial health inequality measured by the Theil index, and between-group variance for OOD rates.ResultsA total of 63 131 simulated individuals were estimated to be at risk for opioid overdose in Rhode Island based on current population data. With the supply-based approach, prioritizing additional naloxone kits to people who use illicit drugs averted more witnessed OODs by an estimated mean of 18.9% (95% simulation interval [SI], 13.1%-30.7%) annually. Expanded naloxone distribution using the demand-based approach and focusing on people who inject drugs had the best outcomes across all scenarios, averting an estimated mean of 25.3% (95% SI, 13.1%-37.6%) of witnessed OODs annually, at the lowest mean incremental cost of $27 312 per OOD averted. Other strategies were associated with fewer OODs averted at higher costs but showed similar patterns of improved outcomes and lower unit costs if kits could be reallocated to areas with greater need. The demand-based approach reduced geospatial inequality in OOD rates in all scenarios compared with the supply-based approach and status quo.Conclusions and RelevanceIn this decision analytical model study, variations in the effectiveness, efficiency, and health inequality of the different naloxone distribution expansion strategies and approaches were identified. Future efforts should be prioritized for people at highest risk for overdose (those who inject drugs or use illicit drugs) and redirected toward areas with the greatest need. These findings may inform future naloxone distribution priority settings.