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Describes an extrinsic-point-based, interactive image-guided neurosurgical system designed at Vanderbilt University, Nashville, TN, as part of a collaborative effort among the Departments of Neurological Surgery, Computer Science, and Biomedical Engineering. Multimodal image-to-image (II) and image-to-physical (IP) registration is accomplished using implantable markers. Physical space tracking is accomplished with optical triangulation. The authors investigate the theoretical accuracy of point-based registration using numerical simulations, the experimental accuracy of their system using data obtained with a phantom, and the clinical accuracy of their system using data acquired in a prospective clinical trial by 6 neurosurgeons at 4 medical centers from 158 patients undergoing craniotomies to respect cerebral lesions. The authors can determine the position of their markers with an error of approximately 0.4 mm in X-ray computed tomography (CT) and magnetic resonance (MR) images and 0.3 mm in physical space. The theoretical registration error using 4 such markers distributed around the head in a configuration that is clinically practical is approximately 0.5-0.6 mm. The mean CT-physical registration error for the: phantom experiments is 0.5 mm and for the clinical data obtained with rigid head fixation during scanning is 0.7 mm. The mean CT-MR registration error for the clinical data obtained without rigid head fixation during scanning is 1.4 mm, which is the highest mean error that the authors observed. These theoretical and experimental findings indicate that this system is an accurate navigational aid that can provide real-time feedback to the surgeon about anatomical structures encountered in the surgical field.