Objective: This longitudinal, observational study examined changes in physical activity and symptoms as correlates of changes in functional limitations and disability across a 6-month period among individuals with multiple sclerosis (MS). Method: Individuals with MS wore an accelerometer for a 7-day period and completed a battery of measures including the Godin Leisure-Time Exercise Questionnaire (Godin & Shephard, 1985), Symptom Inventory (Schwartz, Vollmer, & Lee, 1999), MS-Related Symptom Checklist (Gulick, 1989), and abbreviated Late-Life Function and Disability Inventory (McAuley, Konopack, Motl, Rosengren, & Morris, 2005) at baseline (n = 292) and 6-month follow-up (n = 276). The data were analyzed using panel analysis with latent variables in AMOS 16.0. Results: The standardized coefficients indicated that (a) change in physical activity was associated with residual change in function (β = .22), (b) change in symptoms was associated with residual changes in both function (β = -.29) and disability (γ = -.15), and (c) change in function was associated with residual change in disability (β = .20). Conclusion: Our findings indicate that change in physical activity is associated with change in disability through a pathway that is consistent with Nagi's (1976) Disablement Model and its extension in individuals with MS. © 2009 American Psychological Association.