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Objective: It has been shown that hemoglobinopathies increase the risk of pregnancy complications and placental dysfunction. This could alter the placental analytes examined during prenatal aneuploidy screening. Our objective was to determine whether there is a difference in maternal serum screening results for women with hemoglobin S variants (AS, SS, SC, S/beta thalassemia) compared with women with normal hemoglobin (AA)., Study Design: This is a retrospective cohort study in African-American women receiving aneuploidy screening at MedStar Washington Hospital Center from 2008 to 2015. We evaluated 79 women with hemoglobin S variants (69 AS and 10 sickle cell disease (SCD)) and 79 controls. Descriptive statistics (means, medians, and frequencies) were calculated for each group. For the continuous variables, differences in the averages between the two groups were tested using the t test or Wilcoxon rank sum test. Differences in the averages between three or more groups were tested using the analysis of variance test or the Kruskal-Wallis test., Results: Demographics were similar between cases and controls. The overall screen positive rate for Down syndrome among patients with sickle cell trait (AS) was 3% (2/69). For patients with SCD, the overall screen positive rate was 10% (1/10). None of the women in the control population (AA) has a positive Down syndrome screening result (0/79)., Conclusion: As expected, the screen positive rate in patients with hemoglobin S variants was higher than controls, however, patients with sickle cell trait do not appear to be at an increased risk for false-positive results with serum aneuploidy screening compared with the general population. We did, however, find an increased risk of false-positive quad screen results in patients with sickle cell disease.