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Studies of early child development in sickle cell disease (SCD) have found modest associations between disease-related risks and developmental status in infants and toddlers, but such associations are evident by early elementary school. We screened 4-year-old children with SCD using 2 screening strategies to assess if biomedical risk factors for neurologic disease are related to developmental screening outcomes at this intermediate age.Seventy-seven 4-year-old children with SCD (M = 4.5 yrs, SD = 0.3 yrs) completed developmental screenings at routine hematology visits using child testing (Fluharty Preschool Speech and Language Screenings Test, 2nd edition) and parent-report (Ages and Stages Questionnaire, 2nd edition) procedures. Genotype and other biomedical variables were coded from medical records.Children with higher-risk SCD genotypes (n = 52) showed lower performance than children with lower-risk genotypes (n = 25) on a measure related to neurologic disease risk in older children (syntactic processing); genotype risk was also related to rates of positive screenings on parent-reported developmental milestones (52% positive screenings in high-risk genotypes vs 12% in low-risk genotypes). Screening outcomes were also related to transcranial Doppler ultrasound findings assessing cerebral blood flow.Developmental screening at age 4 may be a useful target age for identifying preschoolers with sickle cell–related neurodevelopmental concerns. Parent report of developmental milestones and behavioral testing each may have a role in screening for children in need of follow-up services to address potential neurodevelopmental effects from SCD.