Objective: To determine the interrelationships between MRI-defined lesion and atrophy measures of spinal cord involvement and brain involvement and their relationships to disability in a small cohort of patients with multiple sclerosis (MS). Background: Although it is known that cervical spinal cord atrophy correlates with disability in MS, it is unknown whether it is the most important determinant when compared to other regions of the central nervous system (CNS). Furthermore, it is not clear to what extent brain and cord lesions and atrophy are related. Design and Methods: 3T MRI of the whole brain and whole spinal cord was obtained in 21 patients with MS, including 18 with relapsing-remitting, one with secondary progressive, one with primary progressive, and one with a clinically isolated syndrome. Brain global gray and white matter volumes were segmented with Statistical Parametric Mapping 8. Spinal cord contour volume was segmented in whole by a semi-automated method with bins assigned to either the cervical or thoracic regions. All CNS volumes were normalized by the intracranial volume. Brain and cord T2 hyperintense lesions were segmented using a semi-automated edge finding tool. Results: Among all MRI measures, only upper cervical spinal cord volume significantly correlated with Expanded Disability Status Scale score (r=-.515,P= .020). The brain cord relationships between whole or regional spinal cord volume or lesions and gray matter, white matter, or whole brain volume or whole brain lesions were generally weak and all nonsignificant. Conclusions and Relevance: In this preliminary study of mildly disabled, treated MS patients, cervical spinal cord atrophy most strongly correlates with physical disability in MS when accounting for a wide range of other CNS measures of lesions and atrophy, including thoracic or whole spinal cord volume, and cerebral gray, white or whole brain volume. The weak relationship between spinal cord and brain lesions and atrophy may suggest that they progress rather independently in patients with MS. © 2011 by the American Society of Neuroimaging.