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Background: Mixed reality (MR), a form of virtual reality (VR), provides an immersive and interactive experience for the user. Given VR's benefits in patients undergoing needle insertion procedures, MR's usability, impact on anxiety, and safety were evaluated in the blood donation setting. Study Design and Methods: Whole blood donors ≥18 years old (yo) were enrolled at two blood centers and provided a MR headset with independently developed software to wear during blood donation. Pre‐ and post‐donation questionnaires were conducted, and reaction data were reviewed. A post‐study questionnaire was also completed by staff who assisted donors with MR. Descriptive statistics, bivariate analyses, and multinomial logistic regression were performed, and p values determined statistical significance between variables. Results: A total of 282 donors completed the study. 84% wanted to try MR because it seemed fun/different/cool/interesting, and most staff (69%) and donors (68%) found MR easy to use. Baseline subjective anxiety, reported by 50.3% (more often in females, first‐time donors, and donors <20 yo), was reduced by MR in 68.4% of donors, and there was a 3.6 times higher odds of anxiety reduction with MR. 54% of donors with baseline anxiety would use MR again with the highest future interest in young donors. Donor reactions while using MR were mild and included pre‐faint reactions and hematomas. Conclusion: This study demonstrates the potential of MR in reducing donor anxiety, its feasibility during blood donation, and its safety in blood donors. MR is an innovative technology that holds promise to increase donor engagement, satisfaction, and retention. [ABSTRACT FROM AUTHOR]