Mechanisms of neutrophil infiltration into the rabbit alveolus have been investigated. Complement activation in the circulation induced pulmonary vascular margination but not a significant level of alveolar infiltration. Instillation of C5 fragments into the airways, however, attracted neutrophils into the alveolar airspaces. The anaphylatoxin-inactive fragment of C5, C5a des Arg, was found to be much more active in this regard than C5a. Furthermore, these fragments were shown to induce the production of a neutrophil-directed chemoctactic factor from pulmonary macrophages, raising the question of whether the C5a des Arg was acting directly to attract neutrophils or indirectly via the macrophage. To substantiate a possible role for C5 and C5 fragments in alveolitis, active C5 was demonstrated in lavage fluids, and macrophage-derived C5 cleaving enzymes have been described. Finally, a route of neutrophil infiltration via migration through the alveolar capillary wall into the interstitium is proposed, and subsequent penetration of the alveolar epithelium out into the airspace.(Am J Pathol 97: 93--110, 1979).