The use of subvoxel registration of serial magnetic resonance images to detect small changes to the brain and its surrounding tissues and fluids is described and the application of this technique to physiological and clinical problems is illustrated. Isotropic T1 weighted volume images were obtained in normal subjects and patients on two or more occasions (including pre- and post-contrast enhancement). The images were segmented and three-dimensional rigid body translation and rotation were used with sinc interpolation to match precisely the images using a chi 2 test and a minimization routine. Accurately registered images produced in this way, as well as subtraction images derived from them, were used to detect change to the brain. A system of image interpretation based on recognition of changes in tissue or fluid signal intensity as well as site, shape and size is described. Changes in position are analysed using a simple model based on the concept of two plateaux of higher and lower signal intensities and a border zone between them. Small changes due to differences in orientation of the head, as well as inhalation of oxygen, carbon dioxide and carbogen were observed in normal subjects. Changes were also observed in patients with head trauma, an astrocytoma and multiple sclerosis. Differences due to contrast enhancement and treatment were seen. In addition, children showed changes due to growth and development.