In recent years, mutual information has proved to be an excellent criterion for registration of intra-individual images from different modalities. Multi-resolution coarse-to-fine optimization was proposed for speeding-up of the registration process. The aim of our work was to further improve registration speed without compromising robustness or accuracy. We present and evaluate two procedures for co-registration of positron emission tomography (PET) and magnetic resonance (MR) images of human brain that combine a multi-resolution approach with an automatic segmentation of input image volumes into areas of interest and background. We show that an acceleration factor of 10 can be achieved for clinical data and that a suitable preprocessing can improve robustness of registration. Emphasis was laid on creation of an automatic registration system that could be used routinely in a clinical environment. For this purpose, an easy-to-use graphical user interface has been developed. It allows physicians with no special knowledge of the registration algorithm to perform a fast and reliable alignment of images. Registration progress is presented on the fly on a fusion of images and enables visual checking during a registration.