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To determine the localization uncertainties associated with 2-dimensional/3-dimensional image registration in comparison to 3-dimensional/3-dimensional image registration in 6 dimensions on a Varian Edge Linac under various imaging conditions.The systematic errors in 6 dimensions were assessed by comparing automatic 2-dimensional/3-dimensional (kV/MV vs computed tomography) with 3-dimensional/3-dimensional (cone beam computed tomography vs computed tomography) image registrations under various conditions encountered in clinical applications. The 2-dimensional/3-dimensional image registration uncertainties for 88 patients with different treatment sites including intracranial and extracranial were evaluated by statistically analyzing 2-dimensional/3-dimensional pretreatment verification shifts of 192 fractions in stereotactic radiosurgery and stereotactic body radiotherapy.The systematic errors of 2-dimensional/3-dimensional image registration using kV–kV, MV–kV, and MV–MV image pairs were within 0.3 mm and 0.3° for the translational and rotational directions within a 95% confidence interval. No significant difference (P > .05) in target localization was observed with various computed tomography slice thicknesses (0.8, 1, 2, and 3 mm). Two-dimensional/3-dimensional registration had the best accuracy when pattern intensity and content filter were used. For intracranial sites, means ± standard deviations of translational errors were −0.20 ± 0.70 mm, 0.04 ± 0.50 mm, and 0.10 ± 0.40 mm for the longitudinal, lateral, and vertical directions, respectively. For extracranial sites, means ± standard deviations of translational errors were −0.04 ± 1.00 mm, 0.2 ± 1.0 mm, and 0.1 ± 1.0 mm for the longitudinal, lateral, and vertical directions, respectively. Two-dimensional/3-dimensional image registration for intracranial and extracranial sites had comparable systematic errors that were approximately 0.2 mm in the translational direction and 0.08° in the rotational direction.The standard 2-dimensional/3-dimensional image registration tool available on the Varian Edge radiosurgery device, a state-of-the-art system, is helpful for robust and accurate target positioning for image-guided stereotactic radiosurgery.