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The efficacy of radiation therapy treatment depends on the patient setup accuracy at each daily fraction. A significant problem is reproducing the patient position during treatment planning for every fraction of the treatment process. We propose and evaluate an intensity based automatic registration method using multiple portal images and the pre-treatment CT volume. We perform both geometric and radiometric calibrations to generate high quality digitally reconstructed radiographs (DRRs) that can be compared against portal images acquired right before treatment dose delivery. We use a graphics processing unit (GPU) to generate the DRRs in order to gain computational efficiency. We also perform a comparative study on various similarity measures and optimization procedures. Simple similarity measure such as local normalized correlation (LNC) performs best as long as the radiometric calibration is carefully …