Amniotic fluid spectrophotometric analysis for bilirubin (delta optical density [ΔOD450], at 450 nm) is used to assess the severity of fetal involvement in isoimmunized pregnancies. Two patients presented with sickle cell anemia and hyperbilirubinemia who also were isoimmunized. The first patient had anti-kell and anti-e antibodies, whereas the second patient had anti-Lewisaand anti-Coltonbantibodies. Delta OD450was elevated in both patients. The difficulty in interpretation of high ΔOD450in the presence of maternal hyperbilirubinemia is stressed. Sickle cell diseased patients are particularly prone to present with this problem. These patients always have hyperbilirubinemia and a relatively high incidence of irregular antibodies because of the numerous blood transfusions they receive. The management of these two patients is presented with suggestions for the use of alternative modalities of monitoring isoimmunized pregnancies in patients with hyperbilirubinemia.