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A comparison of six similarity measures for use in intensity-based two-dimensional-three-dimensional (2-D-3-D) image registration is presented. The accuracy of the similarity measures are compared to a "gold-standard" registration which has been accurately calculated using fiducial markers. The similarity measures are used to register a computed tomography (CT) scan of a spine phantom to a fluoroscopy image of the phantom. The registration is carried out within a region-of-interest in the fluoroscopy image which is user defined to contain a single vertebra. Many of the problems involved in this type of registration are caused by features which were not modeled by a phantom image alone. More realistic "gold-standard" data sets were simulated using the phantom image with clinical image features overlaid. Results show that the introduction of soft-tissue structures and interventional instruments into the phantom image can have a large effect on the performance of some similarity measures previously applied to 2-D-3-D image registration. Two measures were able to register accurately and robustly even when soft-tissue structures and interventional instruments were present as differences between the images. These measures were pattern intensity and gradient difference. Their registration accuracy, for all the rigid-body parameters except for the source to film translation, was within a root-mean-square (rms) error of 0.53 mm or degrees to the "gold-standard" values. No failures occurred while registering using these measures.