The complement system is widely regarded as essential for normal inflammation, not least because of its ability to activate mast cells^,,,,. However, recent studies have called into question the importance of complement in several examples of mast cell-dependent inflammatory responses^,,,. To investigate the role of complement in mast cell-dependent natural immunity, we examined the responses of complement-deficient mice^, to caecal ligation and puncture, a model of acute septic peritonitis^, that is dependent on mast cells and tumour necrosis factor-α (TNF-α). We found that C4- or C3-deficient mice^, were much more sensitive to caecal ligation and puncture than wild-type (WT) controls (100% versus 20% in 24-h mortality, respectively). C3-deficient mice also exhibited reductions in peritoneal mast cell degranulation, production of TNF-α, neutrophil infiltration and clearance of bacteria. Treating the C3-deficient mice with purified C3 protein enhanced activation of peritoneal mast cells, TNF-α production, neutrophil recruitment, opsonophagocytosis of bacteria and resistance to caecal ligation and puncture, confirming that the defects were complement-dependent. These results provide formal evidence that complement activation is essential for the full expression of innate immunity in this mast cell-dependent model of bacterial infection.