Nowadays, information-theoretic similarity measures, especially the mutual information and its derivatives, are one of the most frequently used measures of global intensity feature correspondence in image registration. Because the traditional mutual information similarity measure ignores the dependency of intensity values of neighboring image elements, registration based on mutual information is not robust in cases of low global intensity correspondence. Robustness can be improved by adding spatial information in the form of local intensity changes to the global intensity correspondence. This paper presents a novel method, by which intensities, together with spatial information, i.e., relations between neighboring image elements in the form of intensity gradients, are included in information-theoretic similarity measures. In contrast to a number of heuristic methods that include additional features into the generic mutual information measure, the proposed method strictly follows information theory under certain assumptions on feature probability distribution. The novel approach solves the problem of efficient estimation of multifeature mutual information from sparse high-dimensional feature space. The proposed measure was tested on magnetic resonance (MR) and computed tomography (CT) images. In addition, the measure was tested on positron emission tomography (PET) and MR images from the widely used Retrospective Image Registration Evaluation project image database. The results indicate that multi-feature mutual information, which combines image intensities and intensity gradients, is more robust than the standard single-feature intensity based mutual information, especially in cases of low global intensity correspondences, such as in PET/MR images or significant intensity inhomogeneity.