Polyvalent pneumococcal vaccine and oral penicillin prophylaxis are frequently used in patients with functional or anatomic asplenia to protect them from fulminant Streptococcus pneumoniae sepsis. We studied nasopharyngeal colonization with pneumococci in 34 patients with sickle cell anemia (aged 6 months to 5 years) receiving penicillin prophylaxis and in 63 age- and race-matched comparison patients. Patients with sickle cell anemia had fewer positive initial pneumococcal nasopharyngeal cultures than did the comparison group (14.5% vs 34.4%, P = 0.03) and significantly lower carriage rates during the respiratory illness season of November to March (8.7% vs 40.5%, P = 0.005). Penicillin prophylaxis did not result in emergence of penicillin-resistant pneumococci or in an increased carriage rate of Haemophilus influenzae type b. Our data suggest a mechanism of action for penicillin prophylaxis and provide some evidence for the relative safety of this regimen.