Although the epidemiology and pathophysiology of serious bacterial infection in homozygous sickle cell anemia (SS disease) have become increasingly well understood, information about infection risk and splenic reticuloendothelial function in hemoglobin SC disease is quite limited. Therefore, the type and frequency of invasive bacterial disease were examined in 51 children with SC disease followed for 370 person-years and splenic function was assessed in 31 patients by quantitation of pitted erythrocytes. Seven serious bacterial infections occurred in four of the patients, five due to Streptococcus pneumoniae and two to Haemophilus influenzae. A primary focus of infection was present in all episodes, none of which proved fatal. Although 30 episodes of pneumonia or chest syndrome occurred in 20 of the patients, a bacterial etiology was proven in only three instances. Splenic function was usually impaired, with a mean pit count of 7.1% +/- 8.2% (range 0% to 22.9%). This is significantly greater than normal, but less than pit counts in patients with SS disease or asplenic subjects. Children with SC disease may have a greater risk of bacterial infection than normal children, but their infection rate is not nearly as high as that in patients with SS disease.