This paper describes a robust, fully automated algorithm to register intrasubject 3D single and multimodal images of the human brain. The proposed technique accounts for the major limitations of the existing voxel similarity-based methods: sensitivity of the registration to local minima of the similarity function and inability to cope with gross dissimilarities in the two images to be registered. Local minima are avoided by the implementation of a stochastic iterative optimization technique (fast simulated annealing). In addition, robust estimation is applied to reject outliers in case the images show significant differences (due to lesion evolution, incomplete acquisition, non-Gaussian noise, etc.). In order to evaluate the performance of this technique, 2D and 3D MR and SPECT human brain images were artificially rotated, translated, and corrupted by noise. A test object was acquired under different angles and positions for evaluating the accuracy of the registration. The approach has also been validated on real multiple sclerosis MR images of the same patient taken at different times. Furthermore, robust MR/SPECT image registration has permitted the representation of functional features for patients with partially complex seizures. The fast simulated annealing algorithm combined with robust estimation yields registration errors that are less than 1° in rotation and less than 1 voxel in translation (image dimensions of 128³). It compares favorably with other standard voxel similarity-based approaches.