Cognitive and academic deficits have been identified in school-aged children with sickle cell disease (SCD). However, there have been very few identified studies that examine neuropsychological functioning in preschool-age children with SCD. It is important to understand effects of SCD from a developmental perspective and to consider the contribution of environmental factors in this at-risk population. Neuropsychological functioning of preschool-age children with SCD and no history of overt stroke (n = 26) was examined across several domains (language, immediate memory/brief attention, visuospatial/visuoconstructional, motor/visuomotor). The mean Full Scale IQ for the sample was 89.0. Performance on the Immediate Memory/ Brief Attention domain was significantly higher than the other domains, although the pattern of performance was relatively consistent, with mean standard scores ranging from 88.0 to 95.0. Disease severity was not significantly related to cognitive functioning in this group of young children with SCD. Socioeconomic status (SES) was significantly correlated with most domain scores and, based on regression analyses, accounted for 18% to 47% of the variance in functioning. Psychosocial factors, such as number of children living in the home and parental stress levels, were negatively associated with Motor/Visuomotor skills, and weekly hours in school/day care was positively associated with language-related skills. Results suggest that, at this young age, psychosocial risk factors appear to be appropriate targets for intervention, with the goal of improving long-term outcome in children with SCD. Further investigations should include comparison to a matched control group.