Rapid progression of joint destruction is an indication of poor prognosis in patients with rheumatoid arthritis. Computed tomography (CT) has the potential to serve as a gold standard for joint imaging since it provides high resolution three-dimensional (3D) images of bone structure. The authors have developed a method to quantify erosion volume changes on wrist CT scans. In this article they present a description and validation of the methodology using multiple scans of a hand phantom and five human subjects. An anthropomorphic hand phantom was imaged with a clinical CT scanner at three different orientations separated by a 30-deg angle. A reader used the semiautomated software tool to segment the individual carpal bones of each CT scan. Reproducibility was measured as the root-mean-square standard deviation (RMMSD) and coefficient of variation (CoV) between multiple measurements of the carpal volumes. Longitudinal erosion progression was studied by inserting simulated erosions in a paired second scan. The change in simulated erosion size was calculated by performing 3D image registration and measuring the volume difference between scans in a region adjacent to the simulated erosion. The RMSSD for the total carpal volumes was 21.0 mm3 (CoV = 1.3%) for the phantom, and 44.1 mm3 (CoV = 3.0%) for the in vivo subjects. Using 3D registration and local volume difference calculations, the RMMSD was 1.0-3.0 mm3 The reader time was approximately 5 min per carpal bone. There was excellent agreement between the measured and simulated erosion volumes. The effect of a poorly measured volume for a single erosion is mitigated by the large number of subjects that would comprise a clinical study and that there will be many erosions measured per patient. CT promises to be a quantifiable tool to measure erosion volumes and may serve as a gold standard that can be used in the validation of other modalities such as magnetic resonance imaging.