Activated microglia are closely associated with neuronal damage in Alzheimer's disease. In the present study, neurons exposed to low concentrations of amyloid-β1-42, a toxic fragment of the amyloid-β protein, were killed by microglia in a process that required cell–cell contact. Pre-treating microglia with polyclonal antibodies to the CD14 protein, or treating neurons exposed to amyloid-β1-42 with a CD14-IgG chimera, prevented the killing of amyloid-β1-42 damaged neurons by microglia. Moreover, microglia from CD14 null mice failed to kill amyloid-β1-42 damaged neurons. Increased neuronal survival was accompanied by a significant reduction in the production of interleukin-6 indicative of reduced microglial activation. These results indicate an important role for CD14 in the recognition and subsequent killing of amyloid-β damaged neurons by microglia.