BACKGROUND: Drug-related death is a significant public health challenge in the United States (U.S.). While social capital has emerged as a macro-social construct of interest in understanding the predictors of drug overdose, most research has examined this construct at the individual and neighborhood-level. This ecological study aims to investigate the association between county-level social capital and drug overdose mortality across 50 U.S. states and the District of Columbia. METHODS: County-level social capital, as measured by a social capital index (SCI), was obtained from the U.S. Congress' Social Capital Project. The SCI incorporates indicators related to family structure stability, confidence and trust in institutions, community cohesion, social network structure and volunteerism. County drug overdose mortality data from 2017 to 2019 were obtained from the National Vital Statistics System restricted-use data files. The association between county-level social capital and drug overdose mortality was assessed by multi-level negative-binomial regression models. RESULTS: In a sample of 2,992 counties, SCI ranged from -4.32 standard deviation below to 2.97 standard deviation above the average SCI across counties. After adjusting for covariates, a one standard deviation increase in SCI was associated with a 24 % decrease in drug overdose death rate (adjusted IRR: 0.76
95 % CI: 0.71, 0.81). CONCLUSION: In this study, counties with high social capital had significantly lower rates of drug overdose deaths than counties with low social capital. Policymakers may consider interventions aimed at promoting factors that mediate the effects of social capital on drug overdose mortality, as a way to tackle this public health challenge.