Pneumococcal surface protein A (PspA) and PspC are important virulence factors. Their absence has been shown to allow improved clearance of pneumococci from the blood of mice and to decrease pneumococcal virulence. In the presence of antibody and complement, pneumococci attach to erythrocytes in a process called immune adherence (IA), which facilitates their delivery to, and eventual phagocytosis by, macrophages. It is not known, however, if PspA and PspC affect IA. Using PspA and/or PspC isogenic mutants and complement-deficient mouse sera, we demonstrated that absence of PspA allows greater deposition of C1q and thus increased classical-pathway-mediated C3 deposition. In the absence of both PspA and PspC, there is also a major increase in C1q-independent C3 deposition through the alternative pathway. The latter was observed even though absence of PspC alone did not have a major effect on alternative-pathway-dependent complement deposition. The enhanced complement C3 deposition realized in the absence of PspA alone and in the absence of PspA and PspC resulted in both greatly increased IA to human erythrocytes and improved transfer of pneumococci from erythrocytes to phagocytes. These data provide new insight into how PspA and PspC act in synergy to protect pneumococci from complement-dependent clearance during invasive infection. Copyright © 2007, American Society for Microbiology. All Rights Reserved.