Human C5a anaphylatoxin is known to be a potent mediator of the acute inflammatory response. It serves to trigger a wide variety of neutrophil responses after binding to a specific cellular receptor. We have now demonstrated that this bioactive glycopolypeptide is also bound to a specific receptor found on murine resident peritoneal macrophages, thioglycollate-induced exudate macrophages, and the murine cell line P388D1. The apparent Kd of the C5a receptors. Resident macrophages appear to have an average of 2 x 10(5) binding sites per cell, whereas thioglycollate- induced cells have only 4-5 x 10(4) binding sites. The continuous cell line P388D1 is intermediate between these two cell types, exhibiting 8-10 x 10(4) C5a receptors per cell. Neither murine lymphocytes nor the parent cell line P388 displays a measurable number of C5a receptors. Macrophage receptor-C5a binding interactions are followed by cellular uptake and degradation of 125I-C5a, much as is observed with neutrophils. As demonstrated in another paper, binding of C5a to macrophages results in augmentation of the primary humoral immune response as well as enhancement of mixed lymphocyte reactions. These observations suggest that C5a should not only be considered as an acute inflammatory mediator but as an immunopotentiating modulator as well, thus serving as a critical link between complement activation and subsequent immune responses.