Purpose/Objective(s): To determine if x-ray projection radiation therapy setup images could be used to perform patient identification and detect gross errors in patient setup using a computer algorithm. Materials/Methods: Three patient cohorts treated using a commercially available image guided radiation therapy (IGRT) system were retrospectively analyzed: a group of 100 cranial radiation therapy patients, a group of 100 prostate cancer patients, and a group of 83 patients treated for spinal lesions. In the prostate and cranial patient groups, localizations using image registration were performed between computed tomography (CT) images from radiation therapy planning and setup x-ray images both corresponding to the same patient, and corresponding to different patients. For the group of spinal patients, localizations were performed to the correct vertebral body, and to vertebral bodies off by one from the correct body, using planning CTs and setup x-rays from the same patient. An image similarity measure used by the image registration algorithm of the IGRT system was recorded from the log files of the IGRT system and evaluated as a discriminant for error detection. Results: A threshold value of the similarity measure could be chosen to separate correct and incorrect patient matches and correct and incorrect vertebral body localizations with excellent accuracy for these patient cohorts. A 10-fold cross-validation using linear discriminant analysis yielded misclassification probabilities of 0.000, 0.0045, and 0.014 for the cranial, prostate, and spinal cases respectively. Conclusions: An automated measure of the image similarity between x-ray setup images and corresponding planning CT images could be used to perform automated patient identification and detection of localization errors in radiation therapy treatments. Author Disclosure: J.M. Lamb: None. N. Agazaryan: None. D.A. Low: None.