We tested a hypothesis that children with sickle cell disease who are completely normal by magnetic resonance imaging can still be cognitively impaired, as predicted by a model of diffuse brain injury. Fifty-four patients with hemoglobin SS (average age 10.9 years +/- 2.9 years SD) were examined with the Wechsler Intelligence Scale for Children-III (WISC-III) and were randomly matched by age, race, and gender with healthy children from the Wechsler normative database. Patients were also imaged at 1.5 Tesla with standard imaging sequences. Among 30 patients who were normal by magnetic resonance imaging, there were substantial deficits in Wechsler Full-Scale IQ, Verbal IQ, and Performance IQ (all P < .01) compared with African-American controls. The patient Wechsler Full-Scale IQ was 12.9 points lower than that of controls and decreased as a function of age (probability = .014). The findings suggest that there is diffuse brain injury in patients and that patient deficits increase with age.