A retrospective neuropathologic study of brains from 66 patients with Alzheimer's disease (AD) demonstrated the presence of a vacuolar change (VC) in 50 cases that was virtually indistinguishable histologically from the spongiform change characteristic of Creutzfeldt-Jakob disease (CJD). Indeed, in several instances, there was initial diagnostic confusion with CJD. Unlike the spongiform change in CJD, however, VC was almost entirely restricted to the medial temporal cortex and amygdala. Furthermore, the severity of VC was usually less intense than the spongiform change observed in cases of CJD with severe neurologic impairment. The VC could be readily distinguished from the fine microvacuolation of the upper layers of the isocortex reported in a number of different conditions, including AD. It also differed from the status spongiosus of the cerebral cortex that occurs in advanced AD and CJD as well as in other degenerative diseases. The artifactual rarefaction that occurs in improperly processed paraffin-embedded brain tissue was excluded as a contributory factor to the VC. Since VC does not invariably occur in AD, it conceivably could represent a subtype of this disorder or may represent a variant of the pathologic changes that can occur. Its relationship to CJD or other slow virus disorders is to date unknown but unlikely.