[show abstract][hide abstract] ABSTRACT: Intraoperative imaging modalities are becoming more prevalent in recent years, and the need for integration of these modalities with surgical guidance is rising, creating new possibilities as well as challenges. In the context of such emerging technologies and new clinical applications, a software architecture for cone-beam CT (CBCT) guided surgery has been developed with emphasis on binding open-source surgical navigation libraries and integrating intraoperative CBCT with novel, application-specific registration and guidance technologies. The architecture design is focused on accelerating translation of task-specific technical development in a wide range of applications, including orthopaedic, head-and-neck, and thoracic surgeries. The surgical guidance system is interfaced with a prototype mobile C-arm for high-quality CBCT and through a modular software architecture, integration of different tools and devices consistent with surgical workflow in each of these applications is realized. Specific modules are developed according to the surgical task, such as: 3D-3D rigid or deformable registration of preoperative images, surgical planning data, and up-to-date CBCT images; 3D-2D registration of planning and image data in real-time fluoroscopy and/or digitally reconstructed radiographs (DRRs); compatibility with infrared, electromagnetic, and video-based trackers used individually or in hybrid arrangements; augmented overlay of image and planning data in endoscopic or in-room video; real-time "virtual fluoroscopy" computed from GPU-accelerated DRRs; and multi-modality image display. The platform aims to minimize offline data processing by exposing quantitative tools that analyze and communicate factors of geometric precision. The system was translated to preclinical phantom and cadaver studies for assessment of fiducial (FRE) and target registration error (TRE) showing sub-mm accuracy in targeting and video overlay within intraoperative CBCT. The work culminates in the development of a CBCT guidance system (reported here for the first time) that leverages the technical developments in Carm CBCT and associated technologies for realizing a high-performance system for translation to clinical studies.