A histogram-based segmentation technique was extended to exploit information acquired by manifold MRI techniques. An automated method was used to combine T2-weighted imaging, diffusion-weighted imaging (DWI), and derived maps of the quantitative apparent diffusion coefficient (ADC). DWI allows the early detection of cerebral ischemia, and the calculated ADC value may provide information on pathophysiologic changes. Different optionally shaped clusters were characterized as separate local density maxima in the resultant 3D histogram. Cluster borders were determined by detecting density minima. Distinct but related clusters could be merged in the histogram using the Euclidian distance and a score describing the spatial neighborhood of pixels in the image. In healthy volunteers, gray matter, white matter, muscle, skin, adipose tissue, and cerebrospinal fluid were clearly identified by the automated analysis. In stroke patients, ischemic regions were reliably segmented irrespective of shape, size, and location. The time course of relative ADC changes in ischemic lesions was determined. Results were confirmed by a radiologist. The proposed automatic segmentation algorithm can be used without restrictions for the fast analysis of any multidimensional dataset. The method has proved to be reliable for determining quantities containing information on the physiologic state of tissue, such as the ADC.