In many cases the combined assessment of three-dimensional anatomical and functional images [single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), and computed tomography (CT)] is necessary to determine the precise nature and extent of lesions. It is important, prior to performing the addition, subtraction, or any other combination of the images, that they be adequately aligned and registered either by experienced radiologists via visual inspection, mental reorientation and overlap of slices, or by an automated registration algorithm. To be useful clinically, the latter case requires validation. The human capacity to evaluate registration results visually is limited and time consuming. This paper describes an algorithmic procedure to provide proxy measures for human assessment that discriminate between badly misregistered pairs of brain images and those likely to be clinically useful. The new algorithm consists of four major steps: segmentation of brain and skin/air boundaries, contour extraction, computation of the principal axes, and computation of the registration quality measures from the contour volumes. The test data were MR and CT brain images. The results of the present study indicate that the use of a measure based on the combination of brain and skin contours and a principal axis function is a good first step to reduce the number of badly registered images reaching the clinician.