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OBJECTIVE Recent research on open-label placebos, or placebos administered without deception or concealment, suggests that they can be effective in a variety of conditions. The current research sought to unpack the mechanisms underlying the treatment efficacy of open-label placebos. METHOD A health care provider induced an allergic reaction in 148 participants via a histamine skin prick test. Participants were then exposed to 1 of 4 conditions additively leveraging various mechanisms of open-label placebo treatments: a supportive patient-provider relationship, a medical ritual, positive expectations, and a rationale about the power of placebos. RESULTS There were no main effects of condition on allergic responses. However, participant beliefs about placebos moderated the effect of open-label placebo treatment condition on physiological allergic reactions: the condition including all 4 components of open-label placebos (a supportive patient-provider relationship, a medical ritual, positive expectations, and a rationale about the power of placebos) significantly reduced physiological allergic reaction among participants with a strong belief in placebos compared with participants in the control group. CONCLUSION Participants' beliefs about placebos interact with information from the provider to reduce physiological allergic reactions in response to an open-label placebo treatment. This study underscores the importance of measuring and understanding how participants' beliefs influence outcomes of treatment, and furthers our understanding of when and how open-label placebo treatments work. (PsycINFO Database Record (c) 2019 APA, all rights reserved).