Intratracheal inoculation of dichloromethylene diphosphonate encapsulated in liposomes leads to the rapid accumulation of this drug in alveolar macrophage (AM) phagolysosomes, and the death of the majority of these cells over the ensuing 24–48 hr. The technique is highly selective for phagocytes and has no detectable side‐effects on other cells in the lung. The present experiments demonstrate that following AM depletion, pre‐sensitized animals respond to aerosol challenge via secondary serum IgE (but not IgG) responses, and the accumulation of large numbers of allergen‐specific and non‐specific antibody forming cells in respiratory tract regional lymph nodes and in lung and airway tissues; the latter comprise both IgE and IgG plasma cells, which were detected in the approximate ratio of 2.5:1. Moreover, aerosol challenged AM‐depleted animals develop large mononuclear cell infiltrates in the lung and airways, which includes a substantial CD4⁺ T‐cell component. These results suggest a major role for AM in regulating the magnitude of secondary IgE responses to inhaled allergen.