The automatic analysis of subtle changes between MRI scans is an important tool for assessing disease evolution over time. Manual labeling of evolutions in 3D data sets is tedious and error prone. Automatic change detection, however, remains a challenging image processing problem. A variety of MRI artifacts introduce a wide range of unrepresentative changes between images, making standard change detection methods unreliable. In this study we describe an automatic image processing system that addresses these issues. Registration errors and undesired anatomical deformations are compensated using a versatile multiresolution deformable image matching method that preserves significant changes at a given scale. A nonlinear intensity normalization method is associated with statistical hypothesis test methods to provide reliable change detection. Multimodal data is optionally exploited to reduce the false detection rate. The performance of the system was evaluated on a large database of 3D multimodal, MR images of patients suffering from relapsing remitting multiple sclerosis (MS). The method was assessed using receiver operating characteristics (ROC) analysis, and validated in a protocol involving two neurologists. The automatic system outperforms the human expert, detecting many lesion evolutions that are missed by the expert, including small, subtle changes.