An effective registration framework between preoperative 3D computed tomography and intraoperative 2D x-ray images is crucial in image-guided therapy. In this paper, a novel 2D/3D hierarchical registration framework via principal-directional Fourier transform operator (HRF-PDFTO) is proposed. First, a PDFTO was established to obtain the in-plane translation and rotation invariance. Then, an initial free template-matching approach based on PDFTO was utilized to avoid initial value assignment and expand the capture range of registration. Finally, the hierarchical registration framework, HRF-PDFTO, was proposed to reduce the dimensions of the registration search space from n 6 to n 2. The experimental results demonstrated that the proposed HRF-PDFTO has good performance with an accuracy of 0.72 mm, and a single registration time of 16 s, which improves the registration efficiency by ten times. Consequently, the HRF-PDFTO can meet the accuracy and efficiency requirements of 2D/3D registration in related clinical applications.