Mutual information (MI) is a well-accepted similarity measure for image registration in medical systems. However, MI-based registration faces the challenges of high computational complexity and a high likelihood of being trapped into local optima due to an absence of spatial information. In order to solve these problems, multi-scale frameworks can be used to accelerate registration and improve robustness. Traditional Gaussian pyramid representation is one such technique but it suffers from contour diffusion at coarse levels which may lead to unsatisfactory registration results. In this work, a new multi-scale registration framework called edge preserving multiscale registration (EPMR) was proposed based upon an edge preserving total variation L1 norm (TV-L1) scale space representation. TV-L1 scale space is constructed by selecting edges and contours of images according to their size rather than the intensity values of the image features. This ensures more meaningful spatial information with an EPMR framework for MI-based registration. Furthermore, we design an optimal estimation of the TV-L1 parameter in the EPMR framework by training and minimizing the transformation offset between the registered pairs for automated registration in medical systems. We validated our EPMR method on both simulated mono- and multi-modal medical datasets with ground truth and clinical studies from a combined positron emission tomography/computed tomography (PET/CT) scanner. We compared our registration framework with other traditional registration approaches. Our experimental results demonstrated that our method outperformed other methods in terms of the accuracy and robustness for medical images. EPMR can always achieve a small offset value, which is closer to the ground truth both for mono-modality and multi-modality, and the speed can be increased 5-8% for mono-modality and 10-14% for multi-modality registration under the same condition. Furthermore, clinical application by adaptive gross tumor volume re-contouring for clinical PET/CT image-guided radiation therapy throughout the course of radiotherapy is also studied, and the overlap between the automatically generated contours for the CT image and the contours delineated by the oncologist used for the planning system are on average 90%.