Activation of the complement system is a key event in the pathogenesis of sepsis. Nevertheless, the exact mechanisms remain inadequately understood. In the current study, we examined the role of complement C3 and C5 in sepsis in wild-type and C3- or C5-deficient mice induced by cecal ligation and puncture. When compared to wild-type mice, C5^-/- showed identical survival, and C3^-/- presented significantly reduced survival. Interestingly, this was associated with significant decreases in plasma levels of proinflammatory mediators. Moreover, although septic C3^-/- animals displayed a 10-fold increase of blood-borne bacteria, C5^-/- animals exhibited a 400-fold increase in bacteremia when compared to wild-type mice. These effects were linked to the inability of C5^-/- mice to assemble the terminal membrane attack complex (MAC), as determined by complement hemolytic activity (CH-50). Surprisingly, although negative control C3^-/- mice failed to generate the MAC, significant increases of MAC formation was found in septic C3^-/- mice. In conclusion, our data corroborate that hemolytic complement activity is essential for control of bacteremia in septic mice. Thus, during sepsis, blockade of C5a or its receptors (rather than C5) seems a more promising strategy, because C5a-blockade still allows for MAC formation while the adverse effects of C5a are prevented.—Flierl, M. A., Rittirsch, D., Nadeau, B. A., Day, D. E., Zetoune, F. S., Sarma, J. V., Huber-Lang, M. S., Ward, P. A. Functions of the complement components C3 and C5 during sepsis.