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The development and performance of a system for x-ray cone-beam computed tomography (CBCT) using an indirect-detection flat-panel imager (FPI) is presented. Developed as a bench-top prototype for initial investigation of FPI-based CBCT for bone and soft-tissue localization in radiotherapy, the system provides fully three-dimensional volumetric image data from projections acquired during a single rotation. The system employs a 512×512 active matrix of a-Si:H thin-film transistors and photodiodes in combination with a luminescent phosphor. Tomographic imaging performance is quantified in terms of response uniformity, response linearity, voxel noise, noise-power spectrum (NPS), and modulation transfer function (MTF), each in comparison to the performance measured on a conventional CT scanner. For the geometry employed and the objects considered, response is uniform to within 2% and linear within 1%. Voxel noise, at a level of ~20 HU, is comparable to the conventional CT scanner. NPS and MTF results highlight the frequency-dependent transfer characteristics, confirming that the CBCT system can provide high spatial resolution and does not suffer greatly from additive noise levels. For larger objects and/or low exposures, additive noise levels must be reduced to maintain high performance. Imaging studies of a low-contrast phantom and a small animal (a euthanized rat) qualitatively demonstrate excellent soft-tissue visibility and high spatial resolution. Image quality appears comparable or superior to that of the conventional scanner. These quantitative and qualitative results clearly demonstrate the potential of CBCT systems based upon flat-panel imagers. Advances in FPI technology (e.g., improved x-ray converters and enhanced electronics) are anticipated to allow high-performance FPI-based CBCT for medical imaging. General and specific requirements of kilovoltage CBCT systems are discussed, and the applicability of FPI-based CBCT systems to tomographic localization and image-guidance for radiotherapy is considered. ©2000 American Association of Physicists in Medicine.