The relationship of microglia and astrocytes to deposits of beta-amyloid protein (BAP) was studied in Alzheimer's disease by immunohistochemistry. BAP was detected in forms varying from diffuse amorphous deposits to compact spherical masses. These latter corresponded in frequency and distribution to senile plaques revealed by Bielschowsky and thioflavine S staining. Approximately half the diffuse deposits had no human leukocyte antigen (HLA)-DR-positive reactive microglia associated with them while nearly all compact deposits had single or multiple HLA-DR-positive reactive microglia embedded in their core. Electron microscopy showed these reactive microglia to be in intimate contact with amyloid fibrils. These data suggest that amyloid deposition may precede the activation of microglia.