Naloxone, an opiate antagonist that can avert opiate overdose mortality, has only recently been prescribed to drug users in a few jurisdictions (Chicago, Baltimore, New Mexico, New York City, and San Francisco) in the United States. This report summarizes the first systematic evaluation of large-scale naloxone distribution among injection drug users (IDUs) in the United States. In 2005, we conducted an evaluation of a comprehensive overdose prevention and naloxone administration training program in New York City. One hundred twenty-two IDUs at syringe exchange programs (SEPs) were trained in Skills and Knowledge on Overdose Prevention (SKOOP), and all were given a prescription for naloxone by a physician. Participants in SKOOP were over the age of 18, current participants of SEPs, and current or former drug users. Participants completed a questionnaire that assessed overdose experience and naloxone use. Naloxone was administered 82 times; 68 (83.0%) persons who had naloxone administered to them lived, and the outcome of 14 (17.1%) overdoses was unknown. Ninety-seven of 118 participants (82.2%) said they felt comfortable to very comfortable using naloxone if indicated; 94 of 109 (86.2%) said they would want naloxone administered if overdosing. Naloxone administration by IDUs is feasible as part of a comprehensive overdose prevention strategy and may be a practicable way to reduce overdose deaths on a larger scale.