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To examine whether reduction of negative emotions and associated autonomic activity could explain placebo analgesia, and to test the effect of experimenter gender on the placebo analgesic response.Sixty-three (n = 32 females) students participated in a within-subjects design where subjects were tested on two separate days, one day for the experimental condition (placebo) and one day for the natural history condition. In the experimental condition, the participants received capsules containing lactose with information that the capsules were a high dose of a potent painkiller. In the natural history condition, the procedures were identical except that the placebo capsules were not administrated. The experimenters were blinded to the fact that all participants received placebo. Pain was induced by a thermode holding +46°C with duration of 240 seconds to the forearm. Electrocardiogram was measured to obtain data for analysis of heart rate variability. Subjective measurements consisted of pain intensity, pain unpleasantness, stress, arousal, and mood.The results showed a placebo effect on pain intensity and a concomitant reduction in subjective stress and cardiac activity. Stepwise regressions revealed that reduced subjective stress was the only predictor for the placebo analgesic response. Contrary to our hypothesis, male subjects displayed increased placebo analgesia when a male acted as experimenter.The results indicate that reduced negative emotional activation could be a mechanism in placebo analgesia and that experimenter gender is probably not systematically related to placebo analgesia.