BACKGROUND AND OBJECTIVE: Determining whether multiple sclerosis (MS) causes death is challenging. Our objective was to contrast two frameworks to estimate probabilities of death attributed to MS (P(MS)) and to other causes (P(Other)): the cause-specific framework (CSF) which requires the causes of death and the excess mortality framework (EMF) which does not. METHODS: We used data from the Observatoire Français de la Sclérose en Plaques (OFSEP, n=37,524) and from a comparative subset where causes of death was available (4,004 women with relapsing onset (R-MS)). In CSF, the probabilities were estimated using Aalen-Johansen method. In EMF, they were estimated from the excess mortality hazard, which is the additional mortality among MS patients as compared to the expected mortality in the matched general population. P(MS) were estimated at 30 years of follow-up, i) with both frameworks in the comparative subset, by age group at onset, and ii) with EMF only in the OFSEP population, by initial phenotype, sex and age at onset. RESULTS: In the comparative subset, the estimated 30-year P(MS) were greater using EMF than CSF: respectively 10.9% [95%CI 8.3-13.6] vs 8.7% [6.4-11.8] among the youngest, and 20.4% [11.3-29.5] vs 16.2% [8.7-30.2] for the oldest groups. In the CSF, probabilities of death from unknown causes ranged from 1.5% [0.7-3.0] to 6.4% [2.5-16.4], and even after their reallocation, P(MS) remained lower with CSF than with EMF. The estimated probabilities of being alive were close using the two frameworks and the estimated P(Other) (EMF vs CSF) were 2.6% [2.5-2.6] vs 2.1% [1.2-3.9] and 18.1% [16.9-19.3] vs 26.4% [16.5-42.2] respectively for the youngest and oldest groups. In the OFSEP population, the estimated 30-year P(MS) ranged from 7.5 [6.4-8.7] to 24.0% [19.1-28.9] in R-MS patients and from 25.4 [21.1-29.7] to 36.8% [28.3-45.3] in primary progressive patients, depending on sex and age. DISCUSSION: EMF has the strong advantage of not requiring death certificates, which quality is sub-optimal. Conceptually, it also appears more relevant as it avoids having to state, for each individual, if death was directly or indirectly caused by MS or if it would have occurred anyway, which is especially difficult in such chronic diseases.