Background: Posterior fossa lesions are common in pediatric-onset multiple sclerosis (MS), which is of concern, given the known role of the cerebellum in cognition. Objectives: To investigate the relationship between cerebellar pathology and cognitive function in youth with pediatric-onset MS. Methods: Twenty-eight pediatric-onset relapsing–remitting MS patients (21 girls; mean age 16.2 years; mean disease duration 4.3 years, median Expanded Disability Status Scale 1.25) were compared to 33 age- and sex-matched healthy controls. Participants underwent structural magnetic resonance imaging (MRI) and neuropsychological evaluation to assess intelligence, attention, processing speed, language, visuo-motor integration, and fine-motor dexterity. Associations between cognitive outcomes and cerebellar volume independent of cerebral volume were examined. Results: Cognitive and motor performance of the MS group was reduced relative to controls (all p<0.003). While cerebellar volumes did not differ between groups, cerebellar posterior lobe volume and infratentorial lesion volume accounted for extra variance on measures of information processing (R2=0.43; p=0.02) and vocabulary (R2=0.56; p=0.04) in patients (controlling for cerebral volume and sex), but not in controls. Conclusion: Smaller cerebellar posterior lobe volume, a known region for cognitive processing, and increased lesion burden in the posterior fossa adversely impact cognitive function, an important functional consequence of MS onset during childhood. [ABSTRACT FROM AUTHOR]