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In image-guided spine surgery, robust three-dimensional to two-dimensional (3D–2D) registration of preoperative computed tomography (CT) and intraoperative radiographs can be challenged by the image content mismatch associated with the presence of surgical instrumentation and implants as well as soft-tissue resection or deformation. This work investigates image similarity metrics in 3D–2D registration offering improved robustness against mismatch, thereby improving performance and reducing or eliminating the need for manual masking.