Active immunization against the β-amyloid peptide (Αβ) with vaccines or passive immunization with systemic monoclonal anti-Aβ antibodies reduces amyloid deposition and improves cognition in APP transgenic mice. In this report, intracranial administration of anti-Αβ antibodies into frontal cortex and hippocampus of Tg2576 transgenic APP mice is described. The antibody injection resulted initially in a broad distribution of staining for the antibody, which diminished over 7 d. Although no loss of immunostaining for deposited Aβ was apparent at 4 hr, a dramatic reduction in the Αβ load was discernible at 24 hr and was maintained at 3 and 7 d. A reduction in the thioflavine-S-positive compact plaque load was delayed until 3 d, at which time microglial activation also became apparent. At 1 week after the injection, microglial activation returned to control levels, whereas Αβ and thioflavine-S staining remained reduced. The results from this study suggest a two-phase mechanism of anti-Αβ antibody action. The first phase occurs between 4 and 24 hr, clears primarily diffuse Αβ deposits, and is not associated with observable microglial activation. The second phase occurs between 1 and 3 d, is responsible for clearance of compact amyloid deposits, and is associated with microglial activation. The results are discussed in the context of other studies identifying coincident microglial activation and amyloid removal in APP transgenic animals.