BACKGROUND AND OBJECTIVE: Virtual reality (VR) refers to a computer-generated three-dimensional space in which a surgeon can interact with patient-specific anatomic models for surgical planning. Augmented reality (AR) is the technology that places computer-generated objects, including those made in VR, into the surgeon's visual space. Together, VR and AR are called mixed reality (MxR), and it is gaining importance in neurosurgery. MxR is helpful for selecting and creating templates for an optimal surgical approach and identifying key anatomic landmarks intraoperatively. By reporting our experience with the first 100 consecutive cases planned with VR and executed with AR, our objective is to detail the learning curve and encountered obstacles while adopting the new technology. METHODS: This series includes the first 100 consecutive complex cranial cases of a single surgeon for which MxR was intended for use. Effectiveness of the VR rehearsal and AR guidance was analyzed for four specific contributions: (1) opening size, (2) precise craniotomy placement, (3) guidance toward anatomic landmarks or target, and (4) antitarget avoidance. Seventeen cases in the study cohort were matched with historical non-MxR cases for comparison of outcome parameters. The cases in which MxR failed were plotted over time to determine the nature of the "learning curve." RESULTS: AR guidance was abandoned in eight operations because of technical problems, but problem-free application of MxR increased between the 44th and 63rd cases. This provides some evidence of proficiency acquisition in between. Comparing the 17 pairs of matched MxR and non-MxR cases, no statistically significant differences exist in the groups regarding blood loss, length of stay nor duration of surgery. Cases where MxR had above-expectation performances are highlighted. CONCLUSION: MxR is a powerful tool that can help tailor operations to patient-specific anatomy and provide efficient intraoperative guidance without additional time for surgery or hospitalization.