Background: Histopathologic studies have shown that subpial cortical demyelination is extensive in chronic multiple sclerosis (MS). Objective: To study whether subpial cortical demyelination in MS is associated with focal or diffuse white matter (WM) pathologic features on magnetic resonance imaging (MR imaging). Design: Comparison of postmortem MR imaging findings with histopathologic findings. Setting: Brain donations from a general community. Patients: Three patients with MS with extensive cortical demyelination and 3 patients with minor cortical demyelination were selected from an MS autopsy data set. The postmortem MR imaging and histopathologic data of the patients were compared. Main Outcome Measures: Two observers blinded to the results of each other assessed the presence, extent, and distribution of focal and diffuse pathologic changes in WM by MR imaging and by histopathology. Results: Extensive subpial demyelination was not associated with a significant increase in the area of focal and diffuse WM pathologic changes as assessed by Luxol fast blue histochemistry or by MR imaging or with the presence or extent of juxtacortical abnormalities on MR imaging. Conclusions: The lack of association of MS gray matter demyelination with diffuse or focal WM changes indicates that gray matter demyelination in MS occurs largely independent of WM pathologic changes. The extent or distribution of WM abnormalities cannot be used to identify extensive cortical demyelination in the clinical setting. ©2007 American Medical Association. All rights reserved.