An embodiment in accordance with the present invention provides a technique for localizing structures of interest in projection images (e.g., x-ray projection radiographs or fluoroscopy) based on structures defined in a preoperative 3D image (e.g., MR or CT). Applications include, but are not limited to, spinal interventions. The present invention achieves 3D-2D image registration (and particularly allowing use with a preoperative MR image) by segmenting the structures of interest in the preoperative 3D image and generating a simulated projection of the segmented structures to be aligned with the 2D projection image. Other applications include various clinical scenarios involving 3D-2D image registration, such as image-guided cranial neurosurgery, orthopedic surgery, biopsy, and radiation therapy.