The activation state of the complement system in 39 consecutively admitted patients with systemic meningococcal disease was studied prospectively using two monoclonal antibodies reacting with neoepitopes exposed during complement activation. The fluid-phase C3 activation products and SC5b-9 (terminal complement complex) were strongly correlated to the levels of endotoxin (lipooligosaccharides, LOS) in plasma on admission (r = .79, P less than .0001 and r = .76, P less than .0001, respectively) and to fatality. Maximum complement activation in survivors occurred 7h (median; range 0-44 h) after initiation of antibiotic treatment. The most severely ill patients had the capacity to activate the whole complement cascade. In nonsurvivors, high-grade activation often continued until the patients died. The results suggest that LOS are important activators of complement in systemic meningococcal disease and that complement-activating products, in concert with other mediators, may contribute to the multiple organ failure and death occurring in the most severe cases.