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The HoloLens (Microsoft Corp., Redmond, WA), a head-worn, optically see-through augmented reality (AR) display, is the main player in the recent boost in medical AR research. In this systematic review, we provide a comprehensive overview of the usage of the first-generation HoloLens within the medical domain, from its release in March 2016, until the year of 2021. We identified 217 relevant publications through a systematic search of the PubMed, Scopus, IEEE Xplore and SpringerLink databases. We propose a new taxonomy including use case, technical methodology for registration and tracking, data sources, visualization as well as validation and evaluation, and analyze the retrieved publications accordingly. We find that the bulk of research focuses on supporting physicians during interventions, where the HoloLens is promising for procedures usually performed without image guidance. However, the consensus is that accuracy and reliability are still too low to replace conventional guidance systems. Medical students are the second most common target group, where AR-enhanced medical simulators emerge as a promising technology. While concerns about human–computer interactions, usability and perception are frequently mentioned, hardly any concepts to overcome these issues have been proposed. Instead, registration and tracking lie at the core of most reviewed publications, nevertheless only few of them propose innovative concepts in this direction. Finally, we find that the validation of HoloLens applications suffers from a lack of standardized and rigorous evaluation protocols. We hope that this review can advance medical AR research by identifying gaps in the current literature, to pave the way for novel, innovative directions and translation into the medical routine. [Display omitted] • We review HoloLens 1 usage in medicine from its release in 2016 until 2021. • 217 studies are analyzed according to our novel taxonomy. • We highlight promising applications and most popular research directions. • Major limitations impeding clinical adoption are discussed. • The HoloLens emerges as major driving force in medical AR research in the past years. [ABSTRACT FROM AUTHOR]