Senile plaques found in the Alzheimer's disease brain are foci of local inflammatory reactions mediated by plaque-associated microglia. The interaction of microglia with compacted deposits of β-amyloid (Aβ) fibrils results in the stimulation of intracellular Tyr kinase-based signaling cascades and cellular activation, leading to the secretion of proinflammatory molecules. This study identifies a cell surface receptor complex that mediates the binding of microglia to Aβ fibrils and the subsequent activation of intracellular signaling pathways leading to a proinflammatory response. The receptor complex includes the B-class scavenger receptor CD36, the integrin-associated protein/CD47, and the α₆β₁-integrin. Antagonists of scavenger receptors, CD36, CD47, and α₆β₁ inhibited the adhesion of THP-1 monocytes to Aβ fibrils. In addition, peptide competitors of Aβ fibril interactions with CD36, scavenger receptors, CD47, and the α₆β₁-integrin inhibited Aβ stimulation of Tyr kinase-based signaling cascades in both THP-1 monocytes and murine microglia as well as interleukin 1β production. A scavenger receptor antagonist and antibodies specific for CD36 and the β₁-integrin subunit also inhibited the Aβ-stimulated generation of reactive oxygen species. Importantly, the principal components of this receptor complex are shared with those for other fibrillar proteins and thus represent general elements through which myeloid lineage cells recognize complex fibrillar proteins. Identification of the cell surface molecules that interact with Aβ fibrils and mediate their activation of intracellular signaling cascades represents a potential intervention point in the treatment of Alzheimer's disease.