Background: Fatigue is a common symptom experienced by patients with Multiple Sclerosis (MS); and, the impact of fatigue on work productivity has been documented. However, longitudinal relationships between changes in fatigue and the impact on absenteeism, presenteeism, work productivity, and activity impairment in MS have not been well studied. Objectives: To estimate the impact of change in the symptoms of fatigue using the Fatigue Symptoms and Impacts Questionnaire Relapsing Multiple Sclerosis (FSIQ-RMS) on absenteeism, presenteeism, work productivity, and activity impairment, as assessed by the Work Productivity and Activity Impairment:MS (WPAI:MS), using data from the OPTIMUM trial. Methods: The WPAI:MS and the FSIQ-RMS were administered to patients at baseline, Weeks 12, 24, 60, 84, and 108 with a recall period of 7 days. Based on their FSIQ-RMS fatigue symptom scores (on a scale of 0 100), patients can be categorized into five different levels of severity: none (0 19.4), mild (19.5 31.2), moderate (31.3 46.2), severe (46.3 53.5), and very severe (>53.5). A mixed effect model was used to estimate the effect of experiencing improvements and worsening in fatigue symptoms by 1 or ?2 levels, on changes in each of WPAI outcomes in the overall average across timepoints, while controlling for baseline scores. Results: 1,133 patients with relapsing MS (RMS) were in the OPTIMUM study, 621 (55%) of which were employed at baseline. Among those with WPAI at baseline, the mean percent activity impairment was 33%; employed patients reported a mean of 26% work productivity impairment, with 10% and 23% in absenteeism and presenteeism, respectively. Any level of worsening in fatigue from baseline was significantly (p<0.05) associated with an increase in absenteeism, presenteeism, work productivity loss, and activity impairment, with a greater increase for subjects experiencing ?2 levels of worsening, specifically by 4.0%, 8.3%, 10.2%, and 7.1%, respectively. Improvements by 1 or ? 2 levels in fatigue were found to significantly associated with improvement in activity impairment. Conclusions: Worsening in fatigue symptoms due to MS results in work productivity loss and activity impairment. Improvements in fatigue lead to improvement on overall activity impairment, but not on work productivity loss, which may require a resolution in all symptoms. Disease modifying therapies that reduce the probability of worsening fatigue may result in overall improvements in work productivity and activity impairment in patients with RMS.