BACKGROUND Sickle cell disease (SCD) is a severe hematologic condition that presents unique complications among affected pregnant women. Many studies of adverse perinatal outcomes associated with SCD are limited by small samples or fail to consider important risk factors. PURPOSE This study compared perinatal outcomes among women of African ancestry with and without SCD in a large, population-based sample. METHODS Data from the Massachusetts Pregnancy to Early Life Longitudinal (PELL) Data System were analyzed during June-August 2009 to identify in-state deliveries to resident women of African descent. Logistic regression analyses compared perinatal outcomes for deliveries among women with and without SCD, adjusted for maternal age, education, parity, plurality, insurance status, adequacy of prenatal care, smoking during pregnancy, and infant gender. RESULTS During 1998-2006, there were 116,076 deliveries to 84,561 women; SCD prevalence was 0.6%. Adjusted odds of fetal death among deliveries to women with SCD were 2.2 times those among women without SCD (95% CI=1.2, 4.2). Compared to women without SCD, the odds of preterm delivery, low birth weight, and having babies small for gestational age (SGA) among women with SCD were 1.5 (95% CI=1.2, 1.8); 1.7 (95% CI=1.1, 2.6); and 1.3 (95% CI=1.0, 1.7), respectively. Sickle cell disease was positively associated with cesarean delivery and inductions. CONCLUSIONS Population-based linked data systems are useful for assessing risks of adverse health outcomes among women with specific medical conditions, such as SCD. Women with SCD should seek preconception care to identify and modify risk behaviors and receive counseling regarding potential adverse sequelae associated with pregnancy-related morbidity and preterm delivery.