Direct immunization with amyloidβ protein (Aβ) and passive transfer of anti-Aβ antibodies reduce Aβ accumulation and attenuate cognitive deficits in transgenic models of Alzheimer's disease (AD). The reduction in Aβ deposition has been proposed to involve microglial phagocytosis of Aβ immune complexes via Fc receptors (FcRs). We have examined the efficacy of Aβ immunization in amyloid precursor protein (APP) transgenic mice crossed into FcR-γ chain knock-out mice (FcRγ^-/-). As might be expected from previous studies on macrophages, phagocytosis of Aβ immune complexes via FcR was completely impaired in microglia cells isolated from FcRγ^-/- mice. Thus, we immunized APP Tg2576 transgenic mice that were crossed in the FcRγ^-/- background with Aβ1–42 and then analyzed the effect on Aβ accumulation. In APP Tg2576 transgenic mice crossed to FcRγ^-/-, Aβ1–42 immunization significantly attenuated Aβ deposition, as assessed by both biochemical and immunohistological methods. The reduction in Aβ accumulation was equivalent to the reduction in deposition seen in Aβ1–42 immunized, age-matched, FcR-sufficient Tg2576 mice. We conclude that after Aβ immunization, the effects of anti-Aβ antibodies on Aβ deposition in APP Tg2576 transgenic mice are not dependent on FcR-mediated phagocytic events.