Cerebrum and cerebellum contain numerous asymmetric synapses characterized by the presence of a postsynaptic thickening prominently stained by phosphotungstic acid and other electron-dense stains suitable for electron microscopy. A 51,000-Mr protein, copurified in postsynaptic density-enriched fractions from cerebrum, is considered to be a well established marker for the postsynaptic density. On the basis of two criteria, our studies demonstrate that the 51,000-Mr protein marker for postsynaptic densities is virtually absent in cerebellum, First, it is present in negligible amounts in deoxycholate-insoluble fractions from cerebellum but abundant in parallel fractions from cerebrum. Secondly, the 51,000-Mr protein, which binds 125I-calmodulin after SDS PAGE is readily visualized in membrane samples from cerebrum but is virtually undetectable in cerebellar samples. It is apparent that these results require reexamination of the role of the 51,000-Mr protein in postsynaptic density structures.