Objective: To examine domain-specific neurocognitive differences between African American (AA) and Caucasian (CA) patients with pediatric-onset multiple sclerosis (POMS). Methods: An extensive battery of neuropsychological tests was given to each subject, including tests in all major domains of cognitive function. Point-biserial correlations between ethnicity and test performance were computed. Significant correlations were followed up with hierarchical multiple regression analysis, accounting for clinical and demographic variables before examining ethnic differences. Results: Forty-two patients with POMS including 20 AA and 22 CA subjects were assessed. The cohorts did not differ in age, gender, socioeconomic status, disease duration, disability score, immunoglobulin G index, or number of relapses in the first 2 years of disease. Retaining some of these variables as covariates in the hierarchical regression analysis, the AA cohort performed worse on measures of language (p < 0.001) and complex attention (p < 0.01) than their CA peers. Conclusion: AA patients with POMS may be at higher risk for adverse cognitive impact in the areas of language and complex attention. Longitudinal characterization of cognitive pathology is critical for the development of effective intervention strategies to prolong cognitive functioning in POMS cohorts. © 2010 by AAN Enterprises, Inc. All rights reserved.