Alzheimer's disease (AD) is characterized neuropathologically by the presence of neuritic plaques (NP) in cerebral cortex and hippocampus, as well as intraneuronal neurofibrillary tangles and granulovacuolar degeneration. The etiology of plaque formation has remained obscure, but morphologically NPare known to contain amyloid cores surrounded by astrocytes and degenerating neurons. Although growth factors are important in growth, differentiation and regrowth in response to injury, studies relating growth factors to ADhave been lacking. Epidermal growth factor (EGF) plays an important role outside the central nervous system (CNS) through interaction with its specific receptor, EGF-R. Using an antibody to EGF-R(threestep immunoperoxidase staining) in conjunction with fluorescence staining, we found that the majority of NPfrom patients with pathologically confirmed AD as well as those few NPin the normal aging brain showed intense EGF-Rimmunoreactivity. Specific staining was seen at the periphery of plaques but not in the central amyloid core. Tissue sections from ADcases were also reacted with antibodies to both glial fibrillary acidic protein (GFAP) and paired helical filaments (PHF) in an attempt to identify which component of the NPwas reactive for EGF-R.The antibody to PHFdensely stained the periphery of NP but not the central core in a majority of NP. The antibody to GFAPstained a few reactive astrocytes that bordered plaques in only a small proportion of all plaques present. We conclude that the neuron and its processes although not exclusively may be the site of EGF-Rimmunoreactivity. An EGF/EGF-Rsystem within the CNS may play an important part in scar formation in response to neuronal injury and death or it may function as a trophic factor important in axonal or dendritic sprouting. It is also possible that EGFcould serve as a neurotransmitter/neuromodulator in the CNS