The localization of amyloid precursor protein (APP) in rat brain was studied with a cytoplasmic domain-specific antibody. Light microscopic immunocytochemistry demonstrated that APP is present in most neurons, in some oligodendrocytes, and in a population of cells with diameters less than 10 microns that may be glial. Marked differences in immunoreactivity among neurons were observed, and the strongest immunoreactivity was contained in larger neurons. Neurons with scant cytoplasm, such as granule cells in the olfactory bulb, dentate gyrus, and cerebellum, were weakly immunoreactive. Differences in neuropil immunoreactivity were also observed; this type of staining was strongest in the caudatoputamen, lateral septum, medial habenula, nucleus reticularis of the dorsal thalamus, and the lateral portion of the ventroposterior nucleus. Neuropil immunostaining was weakest in layer IV of cortex and in areas containing granule cells. The fact that APP seems to be present in the vast majority of neurons suggests that this protein plays a role common to all neurons. The fact that there is a great difference in the steady-state amount of APP among different types of neurons suggests that APP may play a specific role in the function of certain classes of neurons.