Keywords Image-guided surgery Ă Cone-beam CT Ă Mobile C-arm Ă Image registration Ă Surgical navigation Purpose Intraoperative 3D imaging with sub-millimeter spatial resolution and soft-tissue visibility is an essential next step in the advancement of precision image-guided surgery. To this end, a prototype mobile C-arm for cone-beam CT (CBCT) has been developed and applied in preclinical studies across a broad spectrum of surgical applications. The current work describes the integration of C-arm CBCT with other image guidance subsystems (including surgical planning, deformable registration, real-time tracking, and visualization) and reports implementation in a prospective clinical trial in head and neck surgery. Methods (a) Integration of C-Arm CBCT guidance systems As illustrated in Fig. 1, the prototype is based on a mobile isocentric C-arm (Siemens PowerMobil) developed in collaboration with Siemens Healthcare. The C-arm was modified to include a flat-panel detector, motorized orbit, geometric calibration, and control system. The system demonstrates 3D image quality with sub-mm spatial resolution and soft-tissue visibility at low radiation dose. Fast 3D reconstruction provides volume images within *15 s of completing the scan.Subsystems ranging from surgical planning to tracking and visualization have been integrated with the C-arm in phased implementation for clinical trials. Fast deformable registration using a multi-scale Demons algorithm transforms preoperative images, the surgical plan, and other intraoperative CBCT to the most recent CBCT image. An adaptive convergence criterion provides accurate registration on a timescale consistent with intra-operative use. Novel real-time tracking developments include: (i) automatic registration of CBCT and tracking systems (eliminating manual registration); and (ii) real-time tracking of endoscopes (augmenting endoscopy with image data and/or virtual representation of the endoscope in CBCT). 3D visualization software developed using the IGSTK library provides triplanar/oblique views, surface and MIP renderings, fusion with preop images and surgical plan, fusion with video endoscopy, and real-time tracking/navigation. (b) Clinical trial in head and neck surgery A prospective trial has been conducted involving 12 patients undergoing surgery of the head and neck. Cases include anterior skull base and sinus tumor resection, maxillectomy, mandibulectomy, and maxillofacial reconstruction. Phase 1 of the trial (6 patients) involved Fig. 1 Systems integrated with C-arm CBCT. a C-arm in the OR. b Surgical target volume registered to CBCT. c Deformable registration showing differences associated with jaw flexion in rigid and deformable registration. d Intraoperative 3D visualization