During the two-year period, 20 Jumada I 1408 (January 9, 1989) to 20 Jumada I 1410 (December 18, 1989), a total of 450 pediatric patients with sickle-cell anemia were admitted to the pediatric ward of Qatif Central Hospital. Thirty-nine patients had a major infection (septicemia, meningitis, or osteomyelitis), with an incidence of 8.6%. During the same period, 3700 non-sickle pediatric patients were admitted and 38 of them had a major infection, with an incidence of 1% (P<0.001). Three patients died in the sickle cell groups, for a case fatality rate of 7.6%, while only one patient in the control group died, for a case fatality rate of 2.6% (P<0.002). Salmonella species were responsible for 12 cases of septicemia and three episodes of osteomyelitis, and Streptococcus pneumoniae was the source in eight cases of septicemia and one case of meningitis in sicklers. Meningitis was caused by different organisms, such as Streptococcus pneumoniae, Salmonella, and Meningococcus. Antibiotics that cover both Salmonella and Streptococcus pneumoniae must be considered in all children with sickle cell anemia who have a febrile illness.