Immunization with pneumococcal capsular polysaccharides (pn PS) is advocated after splenectomy to decrease the risk of overwhelming sepsis. The clinical and experimental evidence for the benefit of immunization after splenectomy is controversial. Various reports in the literature have claimed a benefit of immunization after splenectomy, but careful review of methodologies reveals that heat-killed pneumococci (pn) were used to immunize the experimental animals. Since we have not been able to protect splenectomized (splx) mice by immunization with pn PS, we compared survival after live pneumococcal aerosol challenge and antibody (Ab) responses in splx and sham splx mice immunized with either pn PS or heat-killed pn. Immunization with either heat-killed type 3 pn or pn type 3 PS improved survival in sham-splx mice compared to saline controls (p less than 0.001). Only immunization with heat-killed type 3 pn improved survival in splx mice (p less than 0.001), while pn PS had no effect on survival compared to saline splx controls. Ab responses to pn type 3 PS measured by enzyme linked immunosorbent assay were depressed in splx mice compared to sham-splx mice regardless of the method of immunization. Sham-splx mice immunized with heat-killed pn had higher Ab levels compared to mice vaccinated with pn PS (p less than 0.001) suggesting an adjuvant effect in sham-splx mice. The data suggest that immunization with pn PS may not be beneficial to a splx host. Improved survival after immunization with heat-killed bacteria in splx mice may be related to Ab responses to antigens other than the capsular polysaccharide.