OBJECTIVE: We investigated how augmented reality (AR) can be applied to support transsphenoidal surgery. METHODS: AR was established using the head-up displays integrated into operating microscopes. Navigation registration was performed with either fiducial-based or automatic registration using intraoperative computed tomography (iCT). Correct microscope calibration was ensured by checking the geometric overlap between the AR representation of the reference array and the 3-dimensional reality while focusing on the reference array. RESULTS: From a consecutive single-surgeon series of 288 transsphenoidal procedures, 47 patients (16.3%) had undergone microscope-based AR to visualize the target and risk structures. AR was smoothly integrated into the surgical workflow. AR accuracy depended on navigation accuracy and microscope calibration. The target registration error in patients with fiducial-based registration was 2.33 ± 1.30 mm. Automatic, user-independent iCT-based registration significantly (P < 0.001) increased AR accuracy (target registration error, 0.83 ± 0.44 mm). Applying low-dose iCT protocols reduced the effective dose caused by iCT registration scanning to within the range of a single chest radiograph (0.041 mSv). No vascular injuries and no aggravation of neurological deficits occurred in the present series. AR greatly facilitated orientation in the reoperations and the patients with anatomical variants, thereby increasing surgeon comfort. Enhanced AR visualizations improved the 3-dimensional perception compared with the standard display of dashed lines by the head-up display of the operating microscope. CONCLUSIONS: Microscope-based AR is a reliable tool to increase patient safety in complicated transsphenoidal procedures. Intraoperative imaging-based automatic patient registration is recommended.