Background: The Work Productivity and Activity Impairment (WPAI) questionnaire is a patient-reported outcome that assesses percentage of work time missed, impairment while working, overall work impairment and activity impairment over the last 7 days. Objectives: To report 2-year changes in WPAI, and its association with the 29-item Multiple Sclerosis Impact Scale (MSIS-29) and SymptoMScreen (self-reported symptom burden) among patients with relapsing-remitting MS (RRMS), in the Phase IIIb CASTING trial (NCT02861014). Methods: Patients (N=680; Expanded Disability Status Scale score ?4.0) with a suboptimal response to one or two prior disease-modifying therapies (DMTs) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. WPAI, MSIS-29 and SymptoMScreen were completed at baseline, Week 24, Year 1 and Year 2. Spearman correlations were assessed between change in WPAI subscores from baseline to Year 2, MSIS-29 subscores, and SymptoMScreen total score. Results: WPAI improved from baseline to Year 2, with significant reduction in overall work impairment (?-3.08, p=0.020) and activity impairment (?-5.69, p<0.001), and consistent trends in work time missed (?-2.54, p=0.102) and impairment while working (?-1.66, p=0.129). Improvement in total SymptoMScreen score correlated with a reduction in all WPAI measures: work time missed (rs=0.196), impairment while working (rs=0.387), overall work impairment (rs=0.362) and activity impairment (rs=0.421) over 2 years (all p<0.01). Improvements in MSIS-29 physical and psychological subscores also correlated with reduced work time missed (physical: rs=0.181; psychological: rs=0.198), impairment while working (physical: rs=0.457; psychological: rs=0.361), overall work impairment (physical: rs=0.386; psychological: rs=0.343) and activity impairment (physical: rs=0.524; psychological: rs=0.384) over 2 years (all p<0.01). Conclusions: Patients with a suboptimal response to one or two prior DMTs who switched to ocrelizumab showed improvements in work productivity (WPAI), which correlated with improvement in physical and psychological impacts of MS (MSIS-29) and decrease in overall symptom burden (SymptoMScreen) over 2 years.