In a placebo-controlled, single-blind study we evaluated the ability of three large doses of naloxone (1.0, 5.0, and 10 mg) to antagonize the established respiratory-depressant effects of a common analgesic dose of intravenous buprenorphine (0.3 mg/70 kg). This dose of buprenorphine consistently reduced indexes of CO2 responsiveness to about one half of their control values, much like comparable doses of other opioid analgesics. One milligram of naloxone had little effect on this respiratory depression. Both 5 and 10 mg produced consistent reversal, which was more complete with the larger dose. The reversal effect of naloxone did not occur immediately as is characteristic with morphine and other opioids but rather appeared to reach a maximum 3 hours after reversal. These findings indicate that high doses of naloxone are required to antagonize buprenorphine and naloxone's limited efficacy results not from its short duration of action but rather its relative inability to displace buprenorphine already bound to opioid receptors.