Background: Multiple Sclerosis (MS) is well known to reduce work productivity and adversely affect usual activities. Although previous studies based on cross-sectional data have identified factors (e.g., disability and fatigue) significantly associated with these poor outcomes, none have been found to assess the impact of MS disease activity and change in fatigue on work productivity and regular activity using longitudinal data. Objectives: To estimate the impact of MS disease activity and worsening of fatigue on work productivity and activity impairment (WPAI), as assessed by the WPAI:MS, using data from the phase III OPTIMUM study. Methods: The WPAI:MS, with a recall period of 7 days, is a six-item patient-reported assessment of the amount of absenteeism, presenteeism, overall work productivity, and activity impairment attributable to MS. The instrument was completed in the OPTIMUM study by patients at baseline, Weeks 12, 24, 60, 84, and 108. Fatigue was assessed using the Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS) on the same schedule. A mixed effect model, including all data points, was used to estimate the overall average effect of time-varying covariates, specifically including relapse (yes/no), confirmed disability accumulation (CDA) over 12 and 24 weeks (yes/no), and experience of a worsening in fatigue (yes/no), on each of WPAI outcomes, controlling for relevant covariates. A worsening in fatigue was defined as change from baseline by ? 6.3 points (on a 0 – 100 scale). Results: A total of 1,133 patients with relapsing MS were included in the OPTIMUM study. Among those with WPAI at baseline (n=1,029), the mean percent activity impairment was 33% and, approximately 60% (n=621) were employed, but reported a mean of 26% overall work impairment, with 10% and 23% absenteeism and presenteeism, respectively. Patients having a relapse, worsening in fatigue, or CDA (both 12 and 24 weeks) had a significant negative effect (p<0.05) on each of the WPAI measures, with estimated differences in mean percent of time missed or impaired per week by approximately 5 – 10% more, compared to those not experiencing any of the events. Conclusions: MS disease activity and worsening in fatigue could lead to substantial burden on work productivity loss and activity impairment. Disease modifying therapies reducing these aspects of the disease could yield a considerable positive effect on these outcomes in patients with relapsing MS.