Tobacco smoking has been linked to an increased risk of multiple sclerosis. However, to date, results from the few studies on the impact of smoking on the progression of disability are conflicting. The aim of this study was to investigate the effects of smoking on disability progression and disease severity in a cohort of patients with clinically definite multiple sclerosis. We analysed data from 895 patients (270 male, 625 female), mean age 49 years with mean disease duration 17 years. Forty-nine per cent of the patients were regular smokers at the time of disease onset or at diagnosis (ever-smokers). Average disease severity as measured by multiple sclerosis severity score was greater in ever-smokers, by 0.68 (95% confidence interval: 0.36–1.01). The risk of reaching Expanded Disability Status Scale score milestones of 4 and 6 in ever-smokers compared to never-smokers was 1.34 (95% confidence interval: 1.12–1.60) and 1.25 (95% confidence interval: 1.02–1.51) respectively. Current smokers showed 1.64 (95% confidence interval: 1.33–2.02) and 1.49 (95% confidence interval: 1.18–1.86) times higher risk of reaching Expanded Disability Status Scale scores 4 and 6 compared with non-smokers. Ex-smokers who stopped smoking either before or after the onset of the disease had a significantly lower risk of reaching Expanded Disability Status Scale scores 4 (hazard ratio: 0.65, confidence interval: 0.50–0.83) and 6 (hazard ratio: 0.69, confidence interval: 0.53–0.90) than current smokers, and there was no significant difference between ex-smokers and non-smokers in terms of time to Expanded Disability Status Scale scores 4 or 6. Our data suggest that regular smoking is associated with more severe disease and faster disability progression. In addition, smoking cessation, whether before or after onset of the disease, is associated with a slower progression of disability.