BackgroundThe use of mixed and augmented reality in surgery is a novel and rapidly developing field. Augmented reality is a technology which overlays virtual images on to the real world and is supported by a variety of platforms. Mixed reality is a newer technology, which, in contrast, allows the user to interact with virtual objects projected onto the real world. These technologies have been employed in a range of surgical contexts and specialities and have generated significant public interest, however, the evidence supporting their proposed benefits is unclear. This systematic review aims to critically appraise the intraoperative use of mixed and augmented reality technologies to improve surgical outcomes and provide directions for future research. Methods This systematic review will follow the PRISMA guidelines and search the MEDLINE, EMBASE, the Cochrane Library electronic databases. All clinical studies reporting empirical data on the intraoperative use of augmented or mixed reality technologies will be eligible for inclusion. Identified studies will be screened for inclusion by three authors in parallel, with a fourth author resolving any discrepancies. Risk of bias will be assessed in accordance with Cochrane Handbook for Systematic Reviews of Interventions guidance. The quality of evidence for each outcome will be assessed using the GRADE approach.DiscussionThis will be the first systematic review performed with a specific focus on the use of mixed reality in surgery. If augmented and mixed reality are to become established tools in surgery, it is necessary to understand their use cases, advantages, limitations and cost-effectiveness. This is a young but rapidly evolving field; this synthesis of the current evidence base will provide direction for future research and development.Systematic Review RegistrationPROSPERO CRD42020205892