We compared the growth of Streptococcus pneumoniae mutants with a disruption in the gene for either pneumococcal surface protein A (PspA-), neuraminidase A (NanA-), or hyaluronidase (Hyl-) to that of the parental strain D39 by means of a competitive growth model in mice with and those without prior influenza virus infection. The numbers of total bacteria recovered from mice with prior influenza virus infection were significantly greater than those recovered from mice without prior influenza virus infection. Although the Hyl- and NanA- mutants did not display attenuation in mice with or without prior influenza virus infection, the PspA- mutant exhibited attenuation both in mice with and in mice without prior influenza virus infection. This defect was severe in influenza virus-infected mice, for which growth of the PspA- mutant was 1800-fold lower than that of the parental strain D39. Furthermore, PspA immunization significantly reduced secondary bacterial lung burdens and concentrations of specific markers of lung damage in mice receiving serotypes 2, 3, and 4 pneumococci. Our findings indicate that PspA contributes to secondary S. pneumoniae infection after influenza virus infection and that PspA immunization mitigates early secondary pneumococcal lung infections.