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<h2>Abstract</h2><h3>Background</h3> Patients presenting to the emergency department (ED) following nonfatal opioid overdose represent a high-risk population with 5 % of patients dying within a year of the index visit. <h3>Objective</h3> To evaluate subsequent overdose and death before and after the implementation of an ED discharge naloxone program. <h3>Methods</h3> This was a retrospective cohort study of ED patients who presented at the Virginia Commonwealth University Health ED with an Opioid Use Disorder (OUD) chief complaint before and after a discharge naloxone program. The pre-naloxone cohort was consecutive ED OUD patients from August 15, 2021, to August 14, 2022, and the post-naloxone cohort from August 15, 2022, to August 14, 2023. The outcomes were subsequent overdose, ED visit to same hospital (VCU), and death within six months of the index visit. <h3>Results</h3> In total, 1,053 patients were included, of which 529 were in the pre-naloxone cohort and 524 patients in the post-naloxone cohort. The mean age was 44.2 years (SD = 14.0) and 69 % were males. There was a reduction in overdose requiring ED visiting (subsequent ED overdose) and death (4.6 % vs 9.2 % p = 0.03 and 2.0 % vs 5.6 % p = 0.02 respectively) in the post-naloxone cohort compared to the pre-naloxone cohort. After adjusting for sociodemographic and clinical factors, there was a 48 % reduction in the risk of subsequent ED overdose (RR = 0.52, 95 % CI: 0.27, 1.02) and a 63 % reduction in the risk of death (RR = 0.37, 95 % CI: 0.14, 0.95). <h3>Conclusion</h3> Implementing an ED take-home naloxone program was associated with a reduction in subsequent overdose and death at six months.