Information theoretic-based similarity measures, in particular mutual information, are widely used for intermodal/intersubject 3-D brain image registration. However, conventional mutual information does not consider spatial dependency between adjacent voxels in images, thus reducing its efficacy as a similarity measure in image registration. This paper first presents a review of the existing attempts to incorporate spatial dependency into the computation of mutual information (MI). Then, a recently introduced spatially dependent similarity measure, named spatial MI, is extended to 3-D brain image registration. This extension also eliminates its artifact for translational misregistration. Finally, the effectiveness of the proposed 3-D spatial MI as a similarity measure is compared with three existing MI measures by applying controlled levels of noise degradation to 3-D simulated brain images.