Objective Whether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis. Methods We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity. Results 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43–0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p=10-9) and worsening of disability (0.81, 0.67-0.99, p=0.043). Conclusions Continued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.