ABSTRACT As alarming rates of opioid-related overdose have come to dominate the national dialogue on drug-related harms, the overdose reversal medication naloxone has expanded from the confines of emergency medical personnel to the public domain. The rapid legislative response of many US states to the current epidemic of opioid dependence and overdose has resulted in widespread initiatives to provide naloxone not only to professional first-responders, but also to active opioid users. These initiatives have already demonstrated their worth and are responsible for thousands of overdose reversals and lives saved. To date, however, two important topic areas that bear on the ongoing success of overdose education and naloxone distribution efforts remain unexplored. The first concerns potential gaps in knowledge about and access to naloxone among people who use opioids but are not connected to opioid overdose prevention programs where the bulk of outreach is conducted. The second concerns the largely unexplored behavioral and psychosocial effects of surviving or “reversing” an overdose in which naloxone was administered and of simply having naloxone present while engaging in overdose risk behaviors. Preliminary evidence suggests that these impacts may involve different trajectories depending on individual and social-structural factors. For some, reversing an overdose has been reported to empower individuals to maintain safe opioid use practices. For others, naloxone provision has been met with a self-reported intention to use more opioids. Why naloxone provokes such widely varying responses, and for whom it produces the most robust health benefits, remain critically unexamined questions. To address these public health concerns, this study responds to the current NIDA and FDA mandate for “additional formative and implementation studies of naloxone distribution and overdose intervention in field settings, particularly for prescription opioid abusers.” Using a mixed-method approach designed to yield richly contextualized findings, the proposed study will recruit a sample of 600 people who use illicit opioids in New York City to: a) learn which subgroups of illicit opioid users have been trained in naloxone, used it, or had it used on them, and why some continue to refuse training; b) identify the risk-behavior impacts of using naloxone, surviving an overdose because of naloxone, or having naloxone and a trained overdose responder present when using illicit opioids; and, c) illuminate opioid users’ own perspectives on overdose risk management and naloxone’s role within that, and identify social-structural and psychosocial factors underlying both positive and negative changes in overdose risk behavior. Taken together, these objectives have the power to inform the tailoring and targeting of existing outreach and education strategies and to guide the development of new intervention tools for opioid users whose exposure to naloxone and overdose events may repre...