Asplenic individuals have increased susceptibility to septicemia caused by encapsulated bacteria. Streptococcus pneumoniae, a pathogen carried in the nasal passages of many humans without complication, is responsible for a large proportion of infections seen in asplenic individuals. Our studies have evaluated the efficacy of antibodies to pneumococcal surface protein A (PspA) in protection of asplenic mice. In passive immunity studies, pneumococci were more completely cleared from the blood of splenectomized mice receiving passive antiserum to PspA than those receiving normal rabbit serum. From active mucosal (intranasal) and systemic (subcutaneous) immunizations with rPspA, we determined that the levels of PspA antibodies produced in splenectomized mice were not significantly different from levels seen in mock-splenectomized animals. This active immunity to PspA was able to protect splenectomized mice against death following infection with live pneumococci. Our results suggest that PspA immunization may also protect asplenic humans from pneumococcal infections.