Importance: Despite high rates of drug overdose death among people experiencing homelessness, patterns in drug overdose mortality, including the types of drugs implicated in overdose deaths, remain understudied in this population.

Objective: To describe the patterns in drug overdose mortality among a large cohort of people experiencing homelessness in Boston vs the general adult population of Massachusetts and to evaluate the types of drugs implicated in overdose deaths over a continuous 16-year period of observation.

Design, Setting, and Participants: This cohort study analyzed adults aged 18 years or older who received care at Boston Health Care for the Homeless Program (BHCHP) between January 1, 2003, and December 31, 2017. Individuals were followed up from the date of their initial BHCHP encounter during the study period until the date of death or December 31, 2018. Data were analyzed from December 1, 2020, to June 6, 2021.

Main Outcomes and Measures: Drug overdose deaths and the types of drugs involved in each overdose death were ascertained by linking the BHCHP cohort to the Massachusetts Department of Public Health death records.

Results: In this cohort of 60 092 adults experiencing homelessness (mean [SD] age at entry, 40.4 [13.1] years; 38 084 men [63.4%]), 7130 individuals died by the end of the study period. A total of 1727 individuals (24.2%) died of a drug overdose. Of the drug overdose decedents, 456 were female (26.4%), 194 were Black (11.2%), 202 were Latinx (11.7%), and 1185 were White (68.6%) individuals, and the mean (SD) age at death was 43.7 (10.8) years. The age- and sex-standardized drug overdose mortality rate in the BHCHP cohort was 278.9 (95% CI, 266.1-292.3) deaths per 100 000 person-years, which was 12 times higher than the Massachusetts adult population. Opioids were involved in 91.0% of all drug overdose deaths. Between 2013 and 2018, the synthetic opioid mortality rate increased from 21.6 to 327.0 deaths per 100 000 person-years. Between 2004 and 2018, the opioid-only overdose mortality rate decreased from 117.2 to 102.4 deaths per 100 000 person-years, whereas the opioid-involved polysubstance mortality rate increased from 44.0 to 237.8 deaths per 100 000 person-years. Among opioid-involved polysubstance overdose deaths, cocaine-plus-opioid was the most common substance combination implicated throughout the study period, with Black individuals having the highest proportion of cocaine-plus-opioid involvement in death (0.72 vs 0.62 in Latinx and 0.53 in White individuals; P < .001).

Conclusions and Relevance: In this cohort study of people experiencing homelessness, drug overdose accounted for 1 in 4 deaths, with synthetic opioid and polysubstance involvement becoming predominant contributors to mortality in recent years. These findings emphasize the importance of increasing access to evidence-based opioid overdose prevention strategies and opioid use disorder treatment among people experiencing homelessness, while highlighting the need to address both intentional and unintentional polysubstance use in this population.