Introduction Naloxone, an opiate antagonist that can avert opiate overdose morality, has long been prescribed to drug users in Europe and in a few US cities. However, there has been little documented evidence of naloxone distribution programs and their feasibility in the peer reviewed literature in the US. Methods A pilot overdose prevention and reversal program was implemented in a New York City syringe exchange program. We assessed demographics, drug use, and overdose history, experience, and behavior at baseline, when participants returned for prescription refills, and 3 months after baseline assessment. Results 25 participants were recruited. 22 (88%) participants were successfully followed-up in the first 3 months; of these, 11 (50%) participants reported witnessing a total of 26 overdoses during the follow-up period. Among 17 most-recent overdoses witnessed, naloxone was administered 10 times; all persons who had naloxone administered lived. Discussion Naloxone administration by injection drug users is feasible as part of a comprehensive overdose prevention strategy and may be a practicable way to reduce overdose deaths on a larger scale.