OBJECTIVE: The authors aimed to evaluate the technical feasibility of a mixed-reality neuronavigation (MRN) system with a wearable head-mounted device (HMD) and to determine its clinical application and accuracy. METHODS: A semiautomatic registration MRN system on HoloLens smart glasses was developed and tested for accuracy and feasibility. Thirty-seven patients with intracranial lesions were prospectively identified. For each patient, multimodal imaging-based holograms of lesions, markers, and surrounding eloquent structures were created and then imported to the MRN HMD. After a point-based registration, the holograms were projected onto the patient's head and observed through the HMD. The contour of the holograms was compared with standard neuronavigation (SN). The projection of the lesion boundaries perceived by the neurosurgeon on the patient's scalp was then marked with MRN and SN. The distance between the two contours generated by MRN and SN was measured so that the accuracy of MRN could be assessed. RESULTS: MRN localization was achieved in all patients. The mean additional time required for MRN was 36.3 ± 6.3 minutes, in which the mean registration time was 2.6 ± 0.9 minutes. A trend toward a shorter time required for preparation was observed with the increase of neurosurgeon experience with the MRN system. The overall median deviation was 4.1 mm (IQR 3.0 mm-4.7 mm), and 81.1% of the lesions localized by MRN were found to be highly consistent with SN (deviation < 5.0 mm). There was a significant difference between the supine position and the prone position (3.7 ± 1.1 mm vs 5.4 ± 0.9 mm, p = 0.001). The magnitudes of deviation vectors did not correlate with lesion volume (p = 0.126) or depth (p = 0.128). There was no significant difference in additional operating time between different operators (37.4 ± 4.8 minutes vs 34.6 ± 4.8 minutes, p = 0.237) or in localization deviation (3.7 ± 1.0 mm vs 4.6 ± 1.5 mm, p = 0.070). CONCLUSIONS: This study provided a complete set of a clinically applicable workflow on an easy-to-use MRN system using a wearable HMD, and has shown its technical feasibility and accuracy. Further development is required to improve the accuracy and clinical efficacy of this system.