For the past three decades, neurosurgeons have utilized cranial neuro-navigation systems, bringing millimetric accuracy to operating rooms worldwide. These systems require an operating room team, anesthesia, and, most critically, cranial fixation. As a result, treatments for acute neurosurgical conditions, performed urgently in emergency rooms or intensive care units on awake and non-immobilized ... [Show full abstract] patients, have not benefited from traditional neuro-navigation. These emergent procedures are performed freehand, guided only by anatomical landmarks with no navigation, resulting in inaccurate catheter placement and neurological deficits. A rapidly deployable image-guidance technology that offers highly accurate, real-time registration and is capable of tracking awake, moving patients is needed to improve patient safety. The Zeta Cranial Navigation System is currently the only non-fiducial-based, FDA-approved neuro-navigation device that performs real-time registration and continuous patient tracking. To assess this system’s performance, we performed registration and tracking of phantoms and human cadaver heads during controlled motions and various adverse surgical test conditions. As a result, we obtained millimetric or sub-millimetric target and surface registration accuracy. This rapid and accurate frameless neuro-navigation system for mobile subjects can enhance bedside procedure safety and expand the range of interventions performed with high levels of accuracy outside of an operating room.