We studied the morphology and distribution of substance P-like immunoreactive elements in normal and Alzheimer's disease brain with a monoclonal anti-substance P antibody. Bands of prominent terminal-like staining were found in the dentate gyrus of normal brain. Multipolar substance P-immunoreactive neurons were seen in dentate polymorphic layer and CA4 and prominent fiber staining was present in the CA fields of the hippocampus and adjacent allocortex. Reactive perikarya, concentrated in deep cortex and infracortical white matter, were found in all isocortical regions. Greatest density was in frontal and parietal association cortex; lowest in visual cortex. Fiber density was generally greatest in layers I and II. In Alzheimer's disease, staining intensity was reduced in the dentate gyrus. Hilar neurons were unaffected but other CA field neurons were distorted with pruned dendritic trees. Isocortical perikarya and fibers were significantly depleted and distorted in all regions. Globular deposits consisting of distorted neurites or dissolving perikarya were frequently seen. Double staining methods showed that the vast majority of isocortical, but not hippocampal, substance P-like immunoreactive neurons are nicotinamide adenine dinucleotide phosphate diaphorase-positive. Despite the modest quantitative depletion of substance P in Alzheimer's disease cortex as measured by radioimmunoassay compared to somatostatin, there is a significant depletion of substance P-like immunoreactive perikarya. This disparity may be due to persistence of afferent projections which make a major contribution to substance P concentrations in cerebral cortex or to the high substance P content of dystrophic fibers in Alzheimer's disease cortex.