We observed complement activation in 15 adults undergoing total cardiopulmonary bypass. Plasma levels of C3a were significantly elevated (P < 0.0001) at the beginning of the procedure, and they continued to increase steadily thereafter. At the end of the procedure, C3a levels were more than five times higher than preoperative levels. Plasma levels of C5a (a factor that binds avidly to neutrophils) did not change significantly during cardiopulmonary bypass. Instead, there was significant neutrophilia (P = 0.03) during bypass, and significant transpulmonary neutropenia (P = 0.0002) occurred when cardiopulmonary circulation was reestablished at partial bypass. The neutropenia is consistent with pulmonary-vascular sequestration of C5a-activated granulocytes. We also found that incubation of blood with the nylon-mesh liner of bubble oxygenators, as well as vigorous oxygenation of whole blood, promotes conversion of complement. We conclude that the complement-derived inflammatory mediators C3a and C5a produced during extracorporeal circulation may contribute to the pathogenesis of "post-pump syndromes."