Progressive cerebral deposition of amyloid‐β (Aβ) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease‐implicated proteins can induce antigen‐specific anti‐inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Aβ peptide might induce an anti‐inflammatory process in AD brain tissue that could beneficially affect the neuropathological findings. To test this hypothesis, we treated PDAPP mice, a transgenic line displaying numerous neuropathological features of AD, between the ages of ∼5 and ∼12 months with human Aβ synthetic peptide mucosally each week. We found significant decreases in the cerebral Aβ plaque burden and Aβ42 levels in mice treated intranasally with Aβ peptide versus controls treated with myelin basic protein or left untreated. This lower Aβ burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti‐Aβ antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti‐inflammatory cytokines interleukin‐4, interleukin‐10, and tumor growth factor‐β. Our results demonstrate that chronic nasal administration of Aβ peptide can induce an immune response to Aβ that decreases cerebral Aβ deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD. Ann Neurol 2000;48:567–579