OBJECTIVE The goals of this prospective study were to define the Streptococcus pneumoniae colonization rate in children with sickle cell disease (SCD) at the Children's Hospital of Philadelphia and to determine the serotype and antibiotic susceptibility of all isolates. METHODS Children with SCD followed at the hospital were sampled for colonization with S. pneumoniae by means of a throat or nasopharyngeal swab on one or two occasions. Patient information was obtained when the specimen was collected. Specimens were isolated on gentamicin-blood agar plates and modified Avery broth. Antibiotic susceptibility was determined by a commercially available test (E-test). Isolates were serotyped with the use of type-specific antisera. The relationship between the data noted above and certain clinical parameters was examined. RESULTS A total of 490 specimens were obtained from 278 patients. Twenty-eight patients had a culture positive for S. pneumoniae, resulting in an overall colonization rate of 10%. Thirty-three percent (11/33) of all isolates were resistant to penicillin-seven intermediately resistant and four highly resistant. Twelve percent of isolates were also resistant to cefotaxime. Eight different serotypes were identified; all but one are included in the current 23-valent pneumococcal vaccine. Penicillin prophylaxis did not increase the rate of colonization with resistant strains of pneumococcus. CONCLUSIONS Our results do not support a change in the current use of penicillin prophylaxis nor in the acute management of the febrile child with SCD.