Normal ICR mice were infected intravenously, intraperitoneally, or aerogenically with Pasteurella multocida strains isolated from a turkey (S68), calf (V90), or rabbit (J20) lung. Both the turkey and calf isolates were highly virulent for mice and multiplied logarithmically in the lungs, liver, and spleen, resulting in death of the animals in 18 to 36 h. The rabbit strain was avirulent for mice, but repeated passage in mice did result in some increased virulence. All three strains of P. multocida were inactivated rapidly by normal mouse peritoneal macrophages, provided that the organisms were opsonized with specific hyperimmune serum before being exposed to the macrophage monolayers. P. multocida was slowly inactivated by normal mouse alveolar macrophages when the organisms were preopsonized. However, the surviving organisms later multiplied extensively in vitro. Macrophages harvested from hyperimmunized mice were no better at inactivating opsonized P. multocida cells than were normal mouse cells. The relative importance of the different phagocytic cell populations in the uptake and killing of opsonized P. multocida cells is discussed in relation to immunity to this important animal pathogen.