OBJECTIVES: Phase III clinical trials showed novel drugs introduced in the 1990s modified the natural history (NH) of relapsing-remitting onset definite multiple sclerosis (MS). A Nova Scotia Phase IV 'real world' observational study confirmed the short-term effectiveness of these disease modifying therapies (MS-DMT), measured by Extended Disability Status Scale (EDSS) increase avoided per patient per year. This analysis projects these short-term results over a 20-year horizon to estimate long-term health outcomes of MS-DMT. METHODS: A probabilistic Markov model estimated EDSS progression for NH and MS-DMT cohorts with relapsing-remitting onset MS over a 20-year horizon. The model was based on 591 patients receiving MS-DMT from the Dalhousie MS Research Unit, stratified into three subgroups by final classification and disability severity: 1) mild relapsing-remitting MS (RRMS), 2) mild secondary-progressive MS (SPMS) and 3) mild or moderate SPMS. Health outcomes were measured as EDSS disability adjusted life years (DALYs) avoided per patient compared to NH. Relative benefit was defined as DALY burden avoided relative to expected DALYs given NH. The baseline analysis was a 'best-case' scenario with full compliance for 20 years. RESULTS: The model found statistically significant benefit in all three subgroups. Among the mild severity subgroups, there were 1.7 (95% CI:1.2-2.2) DALYs avoided among RRMS patients and 2.6 (1.5-3.6) DALYs avoided among SPMS patients, for a combined benefit of 1.9 (1.2-3.2) DALYs avoided, or a 42% (20%-91%) relative benefit. Among the mild or moderate SPMS patients there were 1.1 (0.3-1.9) DALYs avoided (14%; 3-30%). Overall, the combined cohort had a benefit of 1.5 (0.5-2.1) DALYs avoided (29%; 6-63%). CONCLUSIONS: MS-DMT can have significant long-term benefit in terms of DALYs avoided, particularly in mild subgroups. This analysis is the first to model long-term change in mean EDSS, rather than delayed time to specific EDSS endpoints, and may help guide MS-DMT coverage decisions.