A system and method for registering pre-operative images of an object with an intra-operative image of the object is disclosed. Prior to an operative procedure, Digitally Reconstructed Radiographs (DRRs) are generated for the pre-operative images of each individual patient. Signatures are extracted from the DRRs. The signatures are stored in a knowledge base. During the operative procedure, a signature is extracted from the intra-operative image. The intra-operative signature is compared to the stored pre-operative signatures. A pre-operative image having a best signature match to the intra-operative signature is retrieved. The retrieved pre-operative image is registered with the intra-operative image.