Background. Prevention of pneumococcal sepsis in children with sickle cell disease (SCD) is threatened by the emergence of penicillin-nonsusceptible pneumococci. Methods. In this study, nasopharyngeal colonization with Streptococcus pneumoniae and penicillin susceptibility were compared in children with SCD and a control group. Nasopharyngeal cultures were obtained from 130 children with SCD and 123 control children. Penicillin susceptibility was determined by Epsilometer test. Compliance with penicillin prophylaxis in SCD patients was determined by parent interviews and review of patients' medical and pharmacy records. Results. Streptococcus pneumoniae was isolated from 8 (6%) of 130 SCD patients, and 21 (17%) of 123 control patients. Of the 29 S pneumoniae isolates, 6 (21%) were nonsusceptible to penicillin; 4 of 8 (50%) were from the SCD group and 2 of 21 (10%) from the control group. Conclusions. Penicillin prophylaxis decreased the rate of S pneumoniae colonization in SCD patients; however, it also increased the risk of selective colonization with penicillin-nonsusceptible S pneumoniae.