Abstract Background Beneficial effects of placebos are high in double-blind hot flush trials. Studies in various conditions suggest that honestly prescribed placebos may elicit symptom improvement. Objective To determine whether open label placebo (OLP) treatment is efficacious in alleviating hot flushes among peri- and postmenopausal women. Methods/design In this assessor-blinded, randomized-controlled trial, n = 100 women experiencing five or more daily hot flushes of at least moderate severity and bothersomeness are assigned 1:1 to a 4-week OLP treatment or no treatment. To explore the duration and maintenance of placebo effects, the OLP group is randomized a second time to either discontinue or continue the OLP treatment for another 4 weeks. All participants receive a briefing about placebo effects and study visits at baseline, post-treatment (4 weeks), and follow-up (8 weeks, OLP group only). Qualitative interviews about subjective experiences with the OLP treatment are conducted. Primary outcomes are differences between the OLP and the no-treatment group in the hot flush composite score (frequency × severity), and bothersomeness of hot flushes as assessed with the Hot Flush Rating Scale at post-treatment. Secondary outcomes include hot flush frequency, health-related quality of life, global improvement, and the number of responders at post-treatment. Data are analyzed by fitting (generalized) linear mixed models. An exploratory analysis of maintenance and duration is performed including follow-up data. Discussion This trial will contribute to the evaluation of OLP treatments in clinical practice and further our understanding about the magnitude of placebo effects in hot flush treatments. Trial registration Clinicaltrials.gov, NCT03838523. Retrospectively registered on February 12th, 2019. The first patient was enrolled on October 10th, 2018.