W e have previously shown a marked difference in the inflammatory response to human C5a or C5a des arginine (Arg) instilled in rabbit lungs. These studies raised the question of where C5a and C5a des Arg are processes in vivo and what role neutrophils may play in the tissue distribution of these two mediators. After intravenous injection of purified, biologically active 125I-C5a or 125I-C5a des Arg, adult rabbits were serially bled and then killed at various time intervals. Although greater than 50% of the injected radioactivity was cleared from the circulation within 2 min for both mediators, C5a des Arg persisted in the circulation longer than C5a. C5a instillation caused an acute neutropenia, whereas C5a des Arg caused a less severe and more prolonged neutropenia, preceding a neutrophilic response observed with both mediators. Clearance of the mediators was primarily seen in the highly vascularized organs: the lung, spleen, liver, and kidney. A time-dependent accumulation was seen initially in the lung, followed by the spleen, liver, and kidney. Histologic examination showed a marked increase in the number of neutrophils within the lung and spleen. Depletion of circulating neutrophils by nitrogen mustard pretreatment of rabbits showed no change in the amount of labeled mediator bound in the lung, whereas splenic accumulation was dependent on the presence of neutrophils. These results indicate that C5a and C5a des Arg are rapidly removed from the circulation by specific accumulation in vascularized tissues. Clearance by the lung was not affected by neutrophil depletion, whereas clearance by the spleen was dependent on neutrophils. These experiments further suggest there are neutrophil-dependent and neutrophil-independent mechanisms involved in the removal of C5a and C5a des Arg from the circulation and that binding of C5 fragments in the pulmonary vasculature may precede and then induce neutrophil sequestration.