Background: Disability progression is a hallmark feature of multiple sclerosis (MS) that has been predicted by a variety of demographic and clinical variables and treatment with disease modifying therapies. This study examined premorbid physical activity as a predictor of change in disability over 24 months in persons with relapsing-remitting MS (RRMS). Methods: 269 persons with RRMS completed baseline measures of demographic and clinical variables, premorbid and current physical activity, and disability status. The measure of disability was further completed every six months over the subsequent 24-month period. The data were analyzed with unconditional and conditional latent growth curve modeling (LGCM). Results: The unconditional LGCM indicated that there was a significant, linear increase in disability scores over time (p=.0015). The conditional LGCM indicated that premorbid physical activity significantly predicted the linear change in disability scores (standardized beta=-.23, p<.005); current physical activity (standardized beta=-.02, p=.81), gender (standardized beta=-.06, p=.54), age (standardized beta=.05, p=.56), duration of MS (standardized beta=.11, p=.15), and treatment with disease modifying therapies (standardized beta=-.03, p=.77) did not predict change in disability scores. Conclusions: The current research highlights the possible role of premorbid physical activity for lessening disability progression over time in persons with RRMS. Additional research is necessary on physical activity initiated after the diagnosis of RRMS as a lifestyle approach for bolstering physiological reserve and preventing disability progression. (C) 2012 Elsevier B.V. All rights reserved.