Motor impairments and cognitive dysfunction are common in multiple sclerosis (MS). We aimed to delineate the relationship between cognitive capacity and upper and lower motor function in 211 MS patients, and 120 healthy volunteers. Lower and upper motor function were assessed with the Timed 25 Foot Walk (T25FW) and the Nine Hole Peg Test (NHPT) as implemented in the Multiple Sclerosis Functional Composite (MSFC). Subjects also underwent neuropsychological evaluation. Hierarchical linear regression analysis was conducted separately for the MS and healthy groups with the T25FW and NHPT serving as the outcome measures. Cognitive performance indices served as predictors. As expected, healthy subjects performed better than the MS group on all measures. Processing speed and executive function tests were significant predictors of lower and upper motor function in both groups. Correlations were more robust in the MS group, where cognitive tests predicted variability in motor function after controlling for disease duration and physical disability. In conclusion, we find evidence of higher order cognitive control of motor function that appears to be particularly salient in this large and representative MS sample. The findings may have implications for risk assessment and treatment of mobility dysfunction in MS. (JINS, 2011, 17, 643–653)