A method to register pairs of portal images quickly and accurately has been developed. The approach uses a cross-correlation operator to find the optimal match between corresponding anatomic regions that have been selected by a user on pairs of portal images. The cross-correlation operator determines the translation that best registers each pair of anatomic features independently, and then the images are translated, rotated, and scaled so that the least squares difference between the coordinates of all of the paired regions is minimized. Tests using simulated images have shown that the accuracy of the algorithm is dependent on (i) the size and shape of the structures within the paired regions; (ii) the subject contrast of the anatomic features being matched; (iii) the rotational difference between the anatomic features; and, (iv) the noise in the image. Tests using contrast-detail phantom images have shown that the semiautomated registration algorithm is only slightly less accurate than human observers, but is considerably faster. The semiautomated algorithm shows great promise as a method of quickly and accurately estimating discrepancies in patient positioning when used in conjunction with an on-line portal imaging system.