Streptococcus pneumoniae is an important bacterial cause of sepsis, meningitis, pneumonia and otitis media. Pneumococcal disease is generally preceded by mucosal colonization with the homologous strain; hence, resistance to colonization may be an important aspect of resistance to disease. In humans, complement deficiency is a risk factor for the development of pneumococcal disease. Although many studies have shown protective effects of complement during pneumonia and meningitis, there have been no studies reported that evaluate the role of complement in containment of pneumococcal colonization. To this end, we studied the role of complement in preventing the progression of pneumococcal mucosal colonization to sepsis in a mouse model. Sepsis developed in 60% of complement-depleted mice following intranasal pneumococcal challenge, but not in control or neutrophil-depleted mice. Colonization density in the nasopharynx and local mucosal tissue was similar between complement-depleted and control mice before onset of sepsis. Immunization of complement-depleted mice with an intranasally administered whole cell pneumococcal vaccine (WCV) reduced progression towards sepsis and protected surviving mice against colonization comparably to complement-sufficient mice. We therefore conclude that complement prevents sepsis following pneumococcal colonization in a neutrophil-independent fashion, but and WCV-induced adaptive immunity is complement-independent.