Background: Buprenorphine is a partial opioid agonist with a reported “ceiling effect” for respiratory depression. Despite implied safety, it has been associated with significant overdoses. Conflicting data exist regarding the response to naloxone. Research Question: How do the clinical characteristics and response to naloxone following buprenorphine overdose compare with those of heroin and methadone overdose? Methods: Consecutive patients admitted to two teaching hospitals with Glasgow Coma Score (GCS) <12 and at least two of the following three criteria were included in this 4year prospective. Observational Study: History suggestive of opioid overdose, pinpoint pupils, or initial respiratory rate <12/min. Demographics, intent, initial GCS, respiratory rate, oxygen saturation (SpO2), and vital signs were collected. Urine toxicological screening was performed and only overdoses involving the exclusive presence of 6-monoacetylmorphine, buprenorphine, or methadone were included. Cases involving multiple opioids were excluded, but cases with benzodiazepine coingestion were allowed. Patients were treated with naloxone and/or flumazenil. Antidote dose and order were at the discretion of the attending physician. Response to naloxone was considered “positive” if full awakening occurred or intubation avoided. Results: During the study, 160 patients were admitted for opioid overdose and 84 met inclusion criteria. These 84 were divided into three groups: heroin (n=26), buprenorphine (n=39), and methadone (n=19). Initial GCS, respiratory rate, SpO2, and blood gas analysis were similar between groups. Benzodiazepine coingestion was more common in the buprenorphine vs heroin group and suicide more common in the methadone vs buprenorphine group. Naloxone was administered in 65% of 84 patients. Buprenorphine-poisoned patients did not respond to 0.4– 0.8 mg intravenous naloxone (0/19). Conclusion: Buprenorphine overdose induced a typical opioid syndrome that was not reversed with naloxone. Critique: The strength of the study was a large number of patients and confirmation of toxins. Weaknesses include lack of data on pinpoint pupils (an inclusion criteria), subjective endpoints, preponderance of benzodiazepine co-ingestions, and lack of detailed naloxone dosing information. Implication for Toxicologists: This study gives further evidence that buprenorphine overdose produces a typical opioid toxidrome. If naloxone is used to treat suspected buprenorphine overdose, doses of 0.4 to 0.8 mg may be insufficient to reverse the clinical effects. Benzodiazepines are common coingestants.