The clinical, epidemiologic, electroencephalographic, and toxicologic features of dialysis encephalopathy (DE) have been clarified, but the neuropathologic and clinicopathologic aspects of the disease have remained obscure. In three cases of DE associated with a dialysate of high aluminum content, spongy change restricted to the upper layers of the cerebral cortex was found. The spongy change was distributed through the cerebral cortex bilaterally and diffusely, but the left hemisphere was involved more severely and extensively than the right hemisphere, and the opercular portions of the frontal and temporal lobes were affected more than the remainder of those lobes. This topographic distribution correlated with the clinical defects in higher cortical functions, including aphasia. The spongy change consisted of vacuoles in the neuropil and inside nerve cell bodies. The vacuoles in the neuropil were located in dendrites, astrocytic processes, and, possibly, other structures. Thus, DE is a disease of neurons and astrocytes of the cerebral cortex. Although spongy change of the upper layers of the cerebral cortex is a nonspecific abnormality, when it occurs in the distribution described and in the absence of other diffuse cerebral diseases, it is characteristic of DE.