Buprenorphine is a partial opioid agonist with a “ceiling effect” for respiratory depression. Despite this, it has been associated with severe overdoses. Conflicting data exist regarding its response in overdose to naloxone. We compared clinical overdose characteristics of buprenorphine with heroin and methadone and assessed responses to naloxone and flumazenil. Patients admitted to two intensive care units with severe opioid overdoses were enrolled into this 4-year prospective study. Urine and blood toxicological screening were performed to identify overdoses involving predominantly buprenorphine, heroin, or methadone. Eighty-four patients with heroin (n = 26), buprenorphine (n = 39), or methadone (n = 19) overdoses were analyzed. In the buprenorphine group, sedative drug coingestions were frequent (95%), whereas in the methadone group, suicide attempts were significantly more often reported (p = .0007). Buprenorphine overdose induced an opioid syndrome not differing significantly from heroin and methadone in mental status (as measured by Glasgow Coma Score) or arterial blood gases. Mental status depression was not reversed in buprenorphine overdoses with naloxone (0.4–0.8 mg) but did improve with flumazenil (0.2–1 mg) if benzodiazepines were coingested. In conclusion, buprenorphine overdose causes an opioid syndrome clinically indistinguishable from heroin and methadone. Although mental status and respiratory depression are often unresponsive to low-dose naloxone, flumazenil may be effective in buprenorphine overdoses involving benzodiazepines.