One-hundred seventy-four children with sickle cell disease (SCD) were immunized with a single dose of tetradecavalent pneumococcal vaccine. Preimmunization and postimmunization antibody against 13 of the 14 pneumococcal capsular antigens was measured by indirect hemagglutination (IHA). The ability of each antigen to stimulate antibody following immunization was characterized by one of three types of responses: (1) poor antibody response regardless of the age at immunization (capsular types 6A, 14, and 19F); (2) improving antibody response with advancing age at immunization (capsular types 1, 4, 9N, 12F, 18C, and 23F); and (3) good antibody response regardless of age at immunization (capsular types 2, 3, 7F, and 8). An increase in antibody following immunization was significantly correlated (P less than 0.0005) with an increasing level of preimmunization antibody titer for all 13 antigens. Through the first 24 months of study, two episodes of pneumococcal sepsis caused by group 23 pneumococci were documented in two children immunized prior to 24 months of age (incidence rate, 4.40/100 patient-years in children less than 5 years of age), and one additional episode caused by a group 23 pneumococcus occurred in a 5 7/12-year-old child (incidence rate, 0.66/100 patient-years in children greater than 5 years of age). These observations suggest that anamnestic immune response significantly contributed to the enhanced antibody response observed in older children and adults. Only modest vaccine efficacy may be expected among children with SCD who receive a single dose of pneumococcal vaccine.