BACKGROUND AND PURPOSE The pathological differences underlying the clinical disease phases in multiple sclerosis (MS) are poorly characterized. We sought to explore the relationship between the distribution of white matter (WM) lesions in relapsing-remitting (RR) and secondary progressive (SP) MS and the normal regional variability of cerebral perfusion. METHODS WM lesions were identified and quantified on a single magnetic resonance imaging scan from 1,249 patients with MS. The spatial distribution of lesions was compared between early RR, late RR, and SP MS in the context of normal cerebral perfusion patterns provided by a single-photon emission-computed tomography atlas of healthy individuals. RESULTS Patients with SP MS had more distinct and larger lesions than patients with RR MS. Across all subjects, lesions were present in regions of relatively lower normal perfusion than normal appearing WM. Further, lesions in SP MS were more common in areas of lower perfusion as compared to the lesion distribution in early and late RR MS. CONCLUSION Chronic plaques were more prevalent in WM regions with lower relative perfusion. Lesions in more highly perfused regions were more commonly observed in early RR MS and therefore, may be more likely to successfully remyelinate and resolve.