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OBJECTIVE The aim of this study was to evaluate our experience with a high-definition three-dimensional (3D) exoscope (EX) for cervical spine surgery versus a binocular operating microscope (OM). METHODS A retrospective review of patients undergoing a single-level anterior cervical discectomy and fusion (ACDF) procedure for the treatment of cervical myelopathy from March 2019 to May 2020 was performed. Demographic, perioperative, and clinical outcomes of 50 patients were included, 23 of whom received assistance from the 3D exoscope (EX group) and 27 of whom received assistance from the OM (OM group). Operative baseline and postoperative outcome parameters were evaluated. Periprocedural handling, visualization, and illumination by the EX, as well as surgeons' ergonomics, were scored using a questionnaire and rapid upper limb assessment (RULA). RESULTS Baseline characteristics were similar between the two groups. There were no significant differences between groups in mean operative time, blood loss, duration of admission, or postoperative improvement of symptoms. Both groups showed similar clinical improvements after surgery. There were no intraoperative complications in either group. According to the attending surgeons, the intraoperative handling of instruments for the EX was rated to be comparable to that of the OM. Surgeons rated the comfort level of the intraoperative posture for the EX as very high on the subjective questionnaire and equal to the OM on the objective RULA. When compared with the OM, depth perception, image quality, and illumination for the EX were rated as inferior in ACDF procedures with long approaches. The operative education and training function of the EX was rated to be superior to that of the OM. CONCLUSIONS Overall, our study showed that the EX appears to be a safe alternative for common ACDF with the unique advantage of excellent comfort and also serves a useful educational tool for the surgical team. However, our investigation revealed several important limitations of this system, including slightly inferior visualization and illumination quality compared with the OM.