To understand the kinematic effects of surgery, arthroplasty or conservative treatments, a noninvasive system to capture accurate 3D imaging of functional activities in prospective, controlled studies is required. To provide such a technique, a new algorithm was developed to register 3D CT data of normal bones to the same bones in a 2D fluoroscopy frame. The algorithm produces a digitally reconstructed radiograph (DRR) from the CT data and then filters this to produce an edge-enhanced image. The resulting image is then registered with an edge-enhanced version of the fluoroscopy frame using a new similarity measure called Cross-Correlation Residual Entropy (CCRE). The system was evaluated by implanting tantalum beads into three cadaveric knees to act as fiducial markers. The knees were flexed between 08 and 708, and single-plane fluoroscopy data of the knees were acquired. CT data of the femur and tibia were then individually registered to the fluoroscopy images. No significant measurement bias was observed, and the standard deviation of the error in bead positions was 0.38 mm for in-plane translation and 0.42 degrees for rotation. To determine the accuracy of the registration algorithm for out-of-plane translations, fluoroscopy frames were scaled in size by fixed increments; the average standard deviation of the errors for out-ofplane translation was 0.65 mm. The ability to obtain such accurate 3D motion data from a noninvasive technique will enable prospective, longitudinal, and controlled studies of reconstruction surgery, and conservative management of joint pathologies. The function of the knee relies on balancing the demands for stability required for weight bearing and protection of the articular tissues, and flexibility required for function in a range of activities.1 This balance is sought between stability and flexibility for rehabilitation after injury, and for total knee replacement kinematics, where improved function and flexibility cannot be at the cost of increased wear. The bony architecture of the knee means it is an inherently unstable joint that relies on soft tissue constraints provided by ligaments, muscle forces, menisci, capsule, and retinaculum to provide guidance to planes of motion and restraints to motion beyond the physiological optimum.2 Indeed, aberrant knee kinematics are responsible for accelerated wear in knee prostheses and in the natural knee, stressing articular cartilage beyond its physiological capacity to respond. 3,4 For the past 20 years, roentgen stereophotogrammetry (RSA) has been the gold standard for mapping 3D kinematics.5 RSA was slow at 2 frames/s; however, dynamic RSA is now capable of acquisition rates of up to 250 frames/s. The major limitation of RSA is that it is invasive, requiring prior implantation of tantalum beads as fiducial markers into the bone. 6 Consequently, it has been mainly used for postoperative studies. Prospective or controlled studies have been rare. 8-10 Previously reported singleplane techniques can be divided into those that explo...