• This matched, case-control study was conducted on 68 neonates with sickle cell disease (SCD) to test the hypothesis that SCD contributes to neonatal jaundice. Previous uncontrolled studies have suggested that SCD leads to a high rate of neonatal jaundice. After matching, two neonates without SCD born in the same year were selected for each patient with SCD by use of random numbers. Matching factors were gestational age, sex, birth weight, and race. Serum bilirubin concentrations and the presence or absence of clinical jaundice were recorded. Information on factors potentially influencing the rate of neonatal jaundice was obtained for the first three days of life: maternal drug, alcohol, and tobacco usage, intrauterine infection, Apgar scores, highest infant hematocrit, culture-proved sepsis, blood group incompatibilities, hemorrhages, and presence of red blood cell sickling. We found no increase in the rate of clinical jaundice and no increase in the bilirubin concentration in either the entire group of patients with SCD, or in the subgroups with either homozygous or S-hemoglobin C disease, compared with their respective controls. We conclude that SCD probably is not a significant factor predisposing to neonatal jaundice.