Complement is important for elimination of invasive microbes from the host, an action achieved largely through interaction of complement-decorated pathogens with various complement receptors (CR) on phagocytes. Pneumococcal surface protein A (PspA) has been shown to interfere with complement deposition onto pneumococci, but to date the impact of PspA on CR-mediated host defense is unknown. To gauge the contribution of CRs to host defense against pneumococci and to decipher the impact of PspA on CR-dependent host defense, wild-type C57BL/6J mice and mutant mice lacking CR types 1 and 2 (CR1/2-/-), CR3 (CH3-/-), or CR4 (CR4-/-) were challenged with WU2, a PspA+ capsular serotype 3 pneumococcus, and its PspA- mutant JY1119. Pneumococci also were used to challenge factor D-deficient (FD-/-), LFA-1-deficient (LFA-1-/-), and CD18-deficient (CD18-/-) mice. We found that FD-/-, CR3-/-, and CR4-/- mice had significantly decreased longevity and survival rate upon infection with WU2. In comparison, PspA- pneumococci were virulent only in FD-/- and CR1/2-/- mice. Normal mouse serum supported more C3 deposition on pneumococci than FD-/- serum, and more iC3b was deposited onto the PspA- than the PspA+ strain. The combined results confirm earlier conclusions that the alternative pathway of complement activation is indispensable for innate immunity against pneumococcal infection and that PspA interferes with the protective role of the alternative pathway. Our new results suggest that complement receptors CR1/2, CM3, and CR4 all play important roles in host defense against pneumococcal infection.