The incidence of functional asplenia in sickle-hemoglobin C (SC) disease has not been defined, and the use of prophylactic penicillin to prevent life-threatening septicemia in this disorder is controversial. The percentage of red blood cells with pits (pit count) is a reliable assay of splenic function in other disorders but has not been validated in hemoglobin SC disease. To address these issues, we conducted a prospective, multicenter study of splenic function in persons with hemoglobin SC disease. Baseline clinical data were recorded, and red blood cell pit counts were performed on 201 subjects, aged 6 months to 90 years, with hemoglobin SC; 43 subjects underwent radionuclide liver-spleen scanning. Pit counts greater than 20% were associated with functional asplenia as assessed by liver-spleen scan, whereas pit counts less than 20% were found in subjects with preserved splenic function. Pit counts greater than 20% were present in 0 of 59 subjects (0%) less than 4 years of age, in 19 of 86 subjects (22%) 4 to 12 years of age, and in 25 of 56 subjects (45%) greater than 12 years of age. Other subjects with hemoglobin SC, who had previously undergone surgical splenectomy, had higher pit counts (59.7% +/- 9.5%) than splenectomized subjects without hemoglobinopathy (38.5% +/- 8.8%) or with sickle cell anemia (20.5% +/- 1.9%; P < .001). Two subjects with hemoglobin SC disease (not splenectomized), ages 14 and 15 years, with pit counts of 40.3% and 41.7% died from pneumococcal septicemia. These data indicate that functional asplenia occurs in many patients with hemoglobin SC disease, but its development is usually delayed until after 4 years of age. The pit count is a reliable measure of splenic function in hemoglobin SC disease, but values indicative of functional asplenia (> 20% in our laboratory) are higher than in other disorders. The routine administration of prophylactic penicillin to infants and young children with hemoglobin SC disease may not be necessary.