The discovery of an endogenous opioid-mediated analgesic system has led to the search for its physiological roles and how it might be activated in natural conditions. Environmental and surgical stress and certain forms of transcutaneous electrical stimulation or acupuncture appear to activate this system. Several studies also suggest that this opioid system mediates placebo analgesia. Placebo reduces post-surgical pain in comparison with no treatment, and this analgesia is apparently reversed by the opioid antagonist, naloxone. However, these studies did not indicate whether naloxone and placebo exert their effects by common or by separate mechanisms. By administering hidden infusions of naloxone (in subjects unaware that the medication was being given) separate from the administration of a placebo, we were able to assess the effects of these two treatments independently. We report here evidence that placebo analgesia can occur after blockade of opioid mechanisms by naloxone and that naloxone can produce hyperalgesia independent of the placebo effect. The combined action of these effects is sufficient to explain the reversal of placebo analgesia by naloxone.