Image-guided radiotherapy (IGRT), adaptive radiotherapy (ART), and online reoptimization rely on accurate mapping of the radiation beam isocenter(s) from planning to treatment space. This mapping involves rigid and/or nonrigid registration of planning (pCT) and intratreatment (tCT) CT images. The purpose of this study was to retrospectively compare a fully automatic approach, including a non-rigid step, against a user-directed rigid method implemented in a clinical IGRT protocol for prostate cancer. Isocenters resulting from automatic and clinical mappings were compared to reference isocenters carefully determined in each tCT. Comparison was based on displacements from the reference isocenters and prostate dose-volume histograms (DVHs). Ten patients with a total of 243 tCTs were investigated. Fully automatic registration was found to be as accurate as the clinical protocol but more precise for all patients. The average of the unsigned x, y, and z offsets and the standard deviations ( σ ) of the signed offsets computed over all images were (avg. ± σ (mm)): 1.1 ± 1.4, 1.8 ± 2.3, 2.5 ± 3.5 for the clinical protocol and 0.6 ± 0.8, 1.1 ± 1.5 and 1.1 ± 1.4 for the automatic method. No failures or outliers from automatic mapping were observed, while 8 outliers occurred for the clinical protocol.