Background Symptom changes may serve as a risk factor for relapse activity (RA) and disability progression (DP), which could facilitate multiple sclerosis (MS) treatment decisions. Objective To assess the relationship of symptom change with RA and DP. Methods We evaluated the relationship of symptom change with subsequent RA and DP using NARCOMS registry data reported over a five-year period. Symptom change was evaluated using both symptom worsening (SW) and average of Performance Scales (APS) scores. Disability progression was defined as a one-point or more increase in Patient-Determined Disease Steps (PDDS) score between two consecutive updates. Repeated measures logistic regression was used to investigate the relationship between symptom change and RA and DP. Results SW and APS were both significant predictors of subsequent RA and DP. Both SW and APS have a significant interaction with levels of disability (Mildly Impaired versus Highly Impaired) for the prediction of the subsequent RA or DP. For Mildly Impaired MS subjects, both SW and APS were significant predictors of both RA and DP. However, for Highly Impaired MS subjects, SW did not significantly predict future RA and neither SW nor APS predicted disability progression. Conclusion Changes in self-reported overall symptomatology may precede and predict clinical relapse and future disability progression. The predictive power of symptom changes may only be present at lower levels of disability.