We present a robust intrasubject registration method for the synergistic use of multiple neuroimaging modalities, with applications to magnetic resonance imaging (MRI), functional MRI, perfusion MRI, MR spectroscopy, and single-photon emission computed tomography (SPECT). This method allows user-friendly processing of difficult examinations (low spatial resolution, advanced pathology, motion during acquisition, and large areas of focal activation). Registration of three-dimensional (3D) brain scans is initially estimated by first-order moment matching, followed by iterative anisotrophic chamfer matching of brain surfaces. Automatic brain surface extraction is performed in all imaging modalities. A new generalized distance definition and new specific methodologies allow registration of scans that cover only a limited range of brain surface. A new semiautomated supervision scheme allows fast and intuitive corrections of possible false automatic registration results. The accuracy of the MRI/SPECT anatomical-functional correspondence obtained was evaluated using simulations and two difficult clinical populations (tumors and degenerative brain disorders). The average discrimination capability of SPECT (12.4 mm in-plane resolution, 20 mm slice thickness) was found to be better than 5 mm after registration with MRI (5 mm slice thickness). Registration accuracy was always better than imaging resolution. Complete 3D MRI and SPECT registration time ranged between 6-11 min, in which surface matching represented 2-3 min. No registration failure occurred. In conclusion, the application of several new image processing techniques allowed efficient and robust registration. Hum.