ABSTRACT Cone beam Computed Tomography (CBCT) with a digital flat panel detector (FPD) is the primary imaging workhorse for image-guided interventions. By rotating the tube-detector assembly around the patient, 3D cone beam CT (CBCT) data can be acquired to supplement 2D x-ray imaging and improve disease diagnosis, treatment planning, and treatment execution in medical procedures. Despite its volumetric coverage and high spatial resolution, FPD-based CBCT does not provide the necessary soft-tissue contrast resolution for intraoperative hemorrhage monitoring, gray-white matter differentiation, or the detection of other low-contrast lesions in a variety of imaging tasks. In addition, quantitative imaging capabilities that are much desired by physicians are lacking in the current CBCT technology. The overarching objective of this project is to develop an integrated PCD-FPD CBCT imaging platform by adding an x-ray photon counting detector (PCD) to the current CBCT system, enabling users to freelyswitch between the new PCD-CBCT imaging mode and the existing FPD-based imaging without interference between the two components. This new imaging platform offers the same soft-tissue contrast resolution and z-coverage as those of MDCT, but without requiring additional room space to house both MDCT and CBCT in the same suite. Additionally, the proposed system offers quantitative spectral CT imaging functionality at reduced radiation and contrast dose for image-guided interventions. To develop the integrated PCD-FPD CBCT imaging system and to explore its added value to medical diagnosis, three specific aims are planned. Aim #1 is designed to construct and calibrate a prototype PCD-CBCT system; Aim #2 is dedicated to the development of the novel correction algorithms needed to achieve artifact-free PCD-CBCT images; Aim #3 is dedicated to clinical feasibility studies using in vivo canine subjects and human subjects. Upon the completion of these aims, a prototype for the next-generation CBCT imaging system will have been constructed, calibrated, and evaluated; the system will be capable of consistently producing nearly artifact-free PCD-CBCT images with spectral imaging functionality and MDCT-like low-contrast detectability; the benefits and potential clinical applications of the integrated PCD-FPD CBCT imaging system will have been demonstrated.