We compared the clinical course of 96 patients with neuromyelitis optica (NMO) to multiple sclerosis (MS) natural history data. Based on the distribution of follow-up data (median 6.1 year), we estimated that 21 NMO patients would convert to a secondary progressive course, but we observed only two conversions (p = 0.00002; relative risk = 0.08). The disparate natural histories of MS and NMO suggest dissociation between relapses and clinical progression in CNS demyelinating diseases.