OBJECTIVE: To determine the effectiveness of intranasal (IN) naloxone compared with intramuscular (IM) naloxone for treatment of respiratory depression due to suspected opiate overdose in the prehospital setting. DESIGN: Prospective, randomised, unblinded trial of either 2 mg naloxone injected intramuscularly or 2 mg naloxone delivered intranasally with a mucosal atomiser. PARTICIPANTS AND SETTING: 155 patients (71 IM and 84 IN) requiring treatment for suspected opiate overdose and attended by paramedics of the Metropolitan Ambulance Service (MAS) and Rural Ambulance Victoria (RAV) in Victoria. MAIN OUTCOME MEASURES: Response time to regain a respiratory rate greater than 10 per minute. Secondary outcome measures were proportion of patients with respiratory rate greater than 10 per minute at 8 minutes and/or a GCS score over 11 at 8 minutes; proportion requiring rescue naloxone; rate of adverse events; proportion of the IN group for whom IN naloxone alone was sufficient treatment. RESULTS: The IM group had more rapid response than the IN group, and were more likely to have more than 10 spontaneous respirations per minute within 8 minutes (82% v 63%; P = 0.0173). There was no statistically significant difference between the IM and IN groups for needing rescue naloxone (13% [IM group] v 26% [IN group]; P = 0.0558). There were no major adverse events. For patients treated with IN naloxone, this was sufficient to reverse opiate toxicity in 74%. CONCLUSION: IN naloxone is effective in treating opiate-induced respiratory depression, but is not as effective as IM naloxone. IN delivery of naxolone could reduce the risk of needlestick injury to ambulance officers and, being relatively safe to make more widely available, could increase access to life-saving treatment in the community.