Lipopolysaccharide and outer membranes from the three virulent encapsulated (Cap(+)) strains of three subspecies of Francisella tularensis and their isogenic avirulent capsule-deficient (Cap(-)) mutants were isolated. It was shown that the Cap cells and their outer membranes almost completely consumed the available complement of normal human serum whereas Cap(-) LPS (R-LPS), Cap(+) cells and their components activated the complement less effectively. Absorption of normal human serum with Cap(-) strain dramatically reduced the complement consumption for homologous strain and its surface structures. This reduction reflected the loss of bactericidal antibodies. Addition of antibodies to whole cells of F. tularensis completely restored complement activity. The cross-absorbing experiments demonstrated that Cap(-) cells more effectively deplete bactericidal antibodies than homologous virulent strain. From these results it can be concluded that normal human serum is bactericidal for serum-sensitive Cap(-) F. tularensis strains through the action of complement initiated by the classical complement pathway and serum resistance of virulent strains is not due to absence of targets for bactericidal antibodies, but is due to their low accessibility because of O-side chains of lipopolysaccharide.