C-reactive protein (CRP) has long been known to be an acute phase protein associated with infection and various forms of tissue damage. Recent studies have shown that human CRP can be used to passively protect mice from lethal infection with Streptococci pneumoniae. In this study we have undertaken a detailed examination of the ability of human CRP and rabbit CRP (CxRP) to mediate the blood clearance of pneumococci in mice. We have shown that the optimal activity of these acute-phase proteins requires a functioning complement system, and it can take place even in the xid mouse, which has virtually no naturally occurring anti-pneumococcal antibody in its serum. These studies provide additional evidence that CRP may play a protective role in pneumococcal infections, and it may help postpone the development of fatal levels of pneumococci in the blood, long enough for an effective anti-pneumococcal antibody response to be generated.