BACKGROUND: Smoking and obesity are recognized modifiable risk factors associated with a higher MS incidence, but their impact on physical and cognitive disability worsening is less clear.OBJECTIVE: To investigate the impact of smoking and obesity on disability worsening in primary progressive MS (PPMS).METHODS: We used data from INFORMS (clinicaltrials.gov identifier: NCT00731692), a large randomized-controlled trial in PPMS to compare significant worsening on the EDSS, T25FW, NHPT, and PASAT between smokers and non-smokers, and between BMI groups, at 12, 24, and 33 months of follow-up. We investigated the association of smoking and BMI at screening and the risk of disability worsening with logistic regression models.RESULTS: Smokers had significantly higher EDSS scores throughout the trial. EDSS was not significantly different between BMI categories. No other outcome measure was significantly different between smokers and non-smokers and between BMI categories throughout the trial. Neither smoking status nor BMI were associated with significant worsening on any outcome measure at any time point during follow-up.CONCLUSION: Despite the known effects on MS incidence, smoking and BMI were not associated with the risk of physical and cognitive disability worsening over 3 years in this well-characterized PPMS trial cohort.