A monoclonal antibody (4D12/2/6) to a synthetic peptide consisting of residues 8-17 of the amyloid beta-protein of Alzheimer's disease was used in an immunohistochemical study to investigate the localization of beta-protein immunoreactivity in neuritic plaques in the brains of 20 cases with Alzheimer's disease and a similar number of nonAlzheimer controls. The morphology and distribution of immunoreactive plaque-like lesions and the sensitivity of immunostaining were assessed both with and without formic acid pretreatment of the sections, and these results were compared with those obtained using conventional Congo red and silver impregnation staining methods. Congo red and immunostaining without formic acid pretreatment mainly stained the core deposits of amyloid in compact plaques, whereas the silver stain could also detect numerous diffuse plaques. Immunostaining with formic acid pretreatment was the most sensitive technique, and this revealed many additional immunoreactive lesions which were impossible or difficult to detect with the other staining methods. These additional lesions included variable sized areas of faint granular staining with little evidence of amyloid deposition or degenerating neurites that are presumed to be very early stages in plaque development. Far fewer immunoreactive lesions were observed in the nonAlzheimer controls. It is concluded that an abundant presence of anti-beta-protein immunoreactive plaque lesions throughout the cortex and subcortical gray matter structures is typical of Alzheimer's disease even when only moderate numbers of plaques can be detected by Congo red or silver stain. This immunostaining procedure with a specific monoclonal antibody for beta-protein may be very useful for the postmortem diagnosis of Alzheimer's disease.