A method for determining differences in patient position between projection radiographs such as those routinely used in radiation therapy has been developed. Determination of a transformation relating two radiographs permits registration of simulation and portal images and the transfer of information between them. The algorithm is based on spatially registering segments of open curves or points seen on both images, and does not require identification of corresponding curve endpoints. The method as implemented is both fast and accurate. After user definition of the curves or points to be registered, the optimal transformation is calculated in approximately 1 s. Calculational experiments indicate that corresponding points on open curves are registered to better than 2 mm, even when random errors (FWHM 1 mm) in digitization are included. Experiments on the registration of clinical portal and simulation images (pixel size = 0.5 by 0.5 mm) indicate an accuracy on the order of 2 mm or less in translation and 2 deg or less in rotation. Analysis of portal and simulation radiographs of the brain, thorax, and pelvis indicates this algorithm to be robust and clinically applicable. The rapid and accurate registration of portal and simulation images is potentially important in the application of real time portal imaging devices in radiation therapy.