OBJECTIVE: Prior investigations have failed to find reliable personality differences in placebo responding. The present study tests the hypothesis that personality and situational variables interact to determine placebo responding. METHODS: Optimists and pessimists were randomly assigned to one of three conditions. In the first condition, the participants were told that they were to ingest a pill that would make them feel unpleasant (deceptive-expectation group). In the second condition, the participants were told that they were to ingest a pill that would make them feel either unpleasant or was an inactive substance (conditional-expectation group). Finally, a third group was told they were to ingest a pill that was inactive (control group). RESULTS: Pessimists were more likely than optimists to follow a negative-placebo expectation when given a deceptive expectation, but not when given a conditional expectation. CONCLUSION: The personality variable optimism-pessimism relates to placebo responding when individuals are given a deceptive but not a conditional expectation. This suggests that personality and situational variables interact to determine placebo responding.