This study was designed to determine the ability of a hemoglobinopathy screening protocol involving sickle solubility testing and red blood cell (RBC) indices to identify at-risk pregnancies. Retrospective chart review of all patients registering for prenatal care at the New York Hospital/Cornell Medical Center prenatal clinic in 1996 was the study design. All patients had RBC indices as well as hemoglobin electrophoresis. RBC indices of those with normal and abnormal electrophoreses were compared. Comparison of protocols involving universal hemoglobin electrophoresis and selective use of hemoglobin electrophoresis were compared. Student's t-test was used for statistical analysis. There were 36 carriers of hemoglobinopathy traits in 631 patients screened (5.7%). Four (three with hemoglobin C trait and one with hemoglobin D trait) had normal RBC indices and presumably would have had negative sickle solubility testing. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a protocol with selective use of hemoglobin electrophoresis would have been 88.9, 79.4, 20.8, and 99.2%, respectively. Cost analysis reveals a difference of $11,384 or $18/patient less in a protocol with selective use of hemoglobin electrophoresis. Although a protocol involving solubility testing with RBC indices will not identify every carrier of a hemoglobinopathy trait, it may be appropriate in some populations.