STUDY OBJECTIVE: Although the World Health Organization recommends take-home naloxone to address the increasing global burden of opioid-related deaths, few emergency departments (EDs) offer a take-home naloxone program. We seek to determine the take-home naloxone acceptance rate among ED patients at high risk of opioid overdose and to examine factors associated with acceptance. METHODS: At a single urban ED, consecutive eligible patients at risk of opioid overdose were invited to complete a survey about opioid use, overdose experience, and take-home naloxone awareness, and then offered take-home naloxone. The primary outcome was acceptance of take-home naloxone, including the kit and standardized patient training. Univariate and multivariable logistic analyses were used to evaluate factors associated with acceptance. RESULTS: Of 241 eligible patients approached, 201 (83.4%) completed the questionnaire. Three-quarters of respondents used injection drugs, 37% were women, and 26% identified as "Indigenous." Of 201 respondents, 137 (68.2%; 95% confidence interval [CI] 61.7% to 74.7%) accepted take-home naloxone. Multivariable analysis revealed that factors associated with take-home naloxone acceptance included witnessing overdose in others (odds ratio [OR] 4.77; 95% CI 2.25 to 10.09), concern about own overdose death (OR 3.71; 95% CI 1.34 to 10.23), female sex (OR 2.50; 95% CI 1.21 to 5.17), and injection drug use (OR 2.22; 95% CI 1.06 to 4.67). CONCLUSION: A two-thirds ED take-home naloxone acceptance rate in patients using opioids should encourage all EDs to dispense take-home naloxone. ED-based take-home naloxone programs have the potential to improve access to take-home naloxone and awareness in individuals most vulnerable to overdoses.