Magnetic resonance imaging (MRI) is emerging as the method of choice for measuring cartilage loss in osteoarthritis (OA), but current methods of analysis are imperfect for therapeutic clinical trials. In this paper, we present and evaluate, in two multicenter multivendor studies, a new method for anatomically corresponded regional analysis of cartilage (ACRAC) that allows analysis of knee cartilage morphology in anatomically corresponding focal regions defined on the bone surface. In our first study, 3-D knee MR Images were obtained from 19 asymptomatic female volunteers, followed by segmentations of the bone and cartilage. Minimum description length (MDL) statistical shape models (SSMs) were constructed from the segmented bone surfaces, providing mean bone shapes and a dense set of anatomically corresponding positions on each individual bone, the accuracy of which were measured using repeat images from a subset of the volunteers. Cartilage thicknesses were measured at these locations along 3-D normals to the bone surfaces, yielding corresponded cartilage thickness maps. Functional subregions of the joint were defined on the mean bone shapes, and propagated, using the correspondences, to each individual. ACRAC improved reproducibility, particularly in the central, load bearing subregions of the joint, compared with measures of volume obtained directly from the segmented cartilage surfaces. In our second study, MR Images were obtained from 31 female patient-volunteers with knee OA at baseline and six months. We obtained manual segmentations of the cartilage, and automatic segmentations of the bone using active appearance models (AAMs) built from the bone SSMs of the first study. ACRAC enabled the detection of significant thickness loss in the central, load-bearing regions of the whole femur (-5.57% p = 0.01, annualized) and the medial condyle (-13.08% , p = 0.024 Bonferroni corrected, annualized). We conclude that statistical shape modelling of bone surfaces defines correspondences invariant to individual joint size or shape, providing focal measures of cartilage with improved reproducibility compared to whole compartment measures. It permits the identification of anatomically equivalent regions, and provides the ability to identify the main load-bearing regions of the joint, based on the imputed premorbid state. The method permitted detection of tiny morphological change in cartilage thickness over six months in a small study, and may be useful for OA disease analysis and treatment monitoring.