Background: Multiple Sclerosis (MS) is a leading cause of disability among young Americans. Reports suggest that life expectancy (i.e., average age at death) remains reduced as compared to the general population, but underlying causes of death (UCOD) are less well-characterized. Objective: To describe the cause-specific mortality among participants enrolled in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry and to compare the profile of these causes by age, sex, race and disability status at entry into NARCOMS, with U.S. mortality data. Methods: The underlying cause of death (UCOD), any mention cause of death and proportionate mortality were compared among U.S. NARCOMS participants by age, sex, race and disability status. Results: Of the 32,445 participants to be considered for this study, 2,927 had died. Compared to survivors, decedents were older at enrollment and MS diagnosis, more likely to be male, and had less education. UCOD differed markedly by age group. In both sexes, MS as the UCOD was proportionately lower by 20% or more in those aged 25-39 compared to those aged 75 or older. Cancer and cardiovascular causes were more frequent as causes of death with increasing age, but were less than expected at older ages. The effect of disability on mortality was roughly equivalent to the effect of aging on mortality. Conclusions: Among NARCOMS participants older age at enrollment, male sex and greater disability were associated with increased mortality risk. This cohort of MS subjects had a lower proportionate mortality from cardiovascular disease and cancer compared to the U.S. population.