Objectives: The main purpose of this study was to measure the effect of a single session of Reiki on physical and psychological health in a large nonclinical sample. Design: The study design was a single arm effectiveness trial with measures at pre-and postintervention. Settings: The study took place at private Reiki practices across the United States. Subjects: Reiki practitioners were recruited from an online mailing list to participate in the study with their Reiki clients. A total of 99 Reiki practitioners met the inclusion criteria and participated in the study. Reiki practitioners were instructed to give a flyer to each of their Reiki clients that contained information about the study and invited the client to complete a survey before and after their Reiki session. Interventions: Trained and certified Reiki Masters conducted the Reiki sessions in person, with each session lasting between 45 and 90 min. Outcome measures: The well-validated 20-item Positive and Negative Affect Schedule was used to assess affect, and brief, single-item self-report measures were used to assess a wide range of physical and psychological variables immediately before (pre) and after (post) the Reiki session. Results: A total of N = 1411 Reiki sessions were conducted and included in the analysis. Statistically significant improvements were observed for all outcome measures, including positive affect, negative affect, pain, drowsiness, tiredness, nausea, appetite, shortness of breath, anxiety, depression, and overall well-being (all p-values <0.001). Conclusions: The results from this large-scale multisite effectiveness trial suggest that a single session of Reiki improves multiple variables related to physical and psychological health.