Nineteen patients were prospectively selected and studied before and after the administration of protamine sulfate following cardiopulmonary bypass (CPB). After protamine administration, C3a, C4a, and C4d were elevated; the peak levels of C3a and C4a were in samples taken 10 minutes after protamine administration while those of C4d were in those obtained at 5 hours. Only C3a was elevated after CPB and before protamine administration. In vitro, only the combination of protamine sulfate and heparin, and neither alone, resulted in increased C3a and C4a. Administration of protamine was associated with small and transient decreases in total white blood cells, granulocytes, and platelets, and with small and transient reductions in systemic and pulmonary arterial and left and right atrial pressures. Systemic vascular resistance fell (p = 0.07), and pulmonary vascular resistance rose but the change could be due to chance (p = 0.29). These data and those reported by others support the inference that complement activation occurs during CPB by the alternative pathway and again during protamine administration by the classic pathway; and that this accompanies a whole-body inflammatory reaction with blood cell and hemodynamic changes which, when extreme, could result in a severe hemodynamic derangement.