OBJECTIVE We investigated the possibility that antimicrobial-resistant pneumococci were causing invasive disease in children with sickle-cell disease (SCD). METHODS Records of all children with SCD observed at the Mid-South Sickle Cell Center (MSSCC) at LeBonheur Children's Medical Center were reviewed from January 1990 to June 1994. Children with SCD and pneumococcal sepsis were identified. The Streptococcus pneumoniae isolates from these children were examined for serotype and antimicrobial susceptibilities. Two additional children not observed in the MSSCC had pneumococcal sepsis caused by penicillin-resistant isolates and were also included. RESULTS Antimicrobial susceptibility testing of the six penicillin-resistant isolates revealed that four were resistant to trimethoprim-sulfamethoxazole, two to erythromycin, and one to clindamycin. The two isolates that were resistant to ceftriaxone also were multiply resistant. From the MSSCC, 26 children had pneumococcal sepsis during the 4 1/2-year period studied. Five of these children (19%) died. Four (15%), including one who died, were infected with penicillin-resistant strains. CONCLUSIONS Pneumococcal sepsis, meningitis, and infections of other foci in children with SCD may be caused by S. pneumoniae that is resistant to one or more antimicrobial agents, including penicillin. The addition of vancomycin to the antibiotics currently used for initial management should be considered in areas where the antibiotic resistance of S. pneumoniae is prevalent.