Diffuse senile plaques are characterized by the presence of beta protein (beta P), also called A4 protein, in a dispersed form and the apparent lack of associated dystrophic neurites or reactive glial cells. They are the most common type of senile plaque found in the cerebral cortex in Alzheimer's disease (AD), Down's syndrome (DS), and normal aging. Here is reported the frequent presence of diffuse senile plaques in the molecular layer of cerebellar cortex in AD. Typical neuritic plaques were never detected in this location, making the cerebellar molecular cortex a useful site for the study of diffuse plaques because diffuse plaques in the cerebral cortex are intermingled with neuritic plaques. Diffuse cerebellar plaques were detected by modified Bielschowsky silver stain in 47 of 100 cases of clinically and pathologically diagnosed AD and in none of 40 aged demented and nondemented controls. They were immunolabeled by antibodies to purified AD meningeal or cortical beta P, and to a synthetic beta P but not by two antibodies to the carboxyl- and amino-termini of the beta protein precursor (beta PP), which label a subgroup of cerebral cortical plaques. This latter result suggests that the beta P deposited in the cerebellar molecular layer may be derived from a form of the beta PP from which the carboxyl and amino terminal regions of the precursor have already been cleaved. Diffuse cerebellar plaques were not recognized by antibodies to neurofilaments, tau, and PHF, all of which detect dystrophic neurites in cerebral cortical neuritic plaques. Also, no association of reactive astrocytes or microglial cells with diffuse cerebellar plaques was observed. Thus, diffuse cerebellar plaques represent multifocal deposits of noncompacted beta P that cause little or no morphologic reaction in their microenvironment.