OBJECTIVES: ASCEND is a phase 3, randomized, double-blind, placebo-controlled trial designed to assess whether natalizumab slows disability progression in secondary progressive multiple sclerosis (SPMS). The objective of this study was to use Rasch Measurement Theory (RMT) methods to evaluate the Multiple Sclerosis Impact Scale (MSIS-29) and MS Walking Scale (MSWS-12), patient-reported outcome instruments assessing the impact of MS, and to explore an optimized scoring structure based on empirical post-hoc analyses METHODS: Baseline blinded data from ASCEND (n=889) were analyzed. In stage 1, RMT methods examined: scale-to-sample targeting, item fit, local dependency, and reliability. In stage 2, a post-hoc revision of the scoring structure (MSIS-29 and MSWS-12) and conceptual grouping of items (MSIS-29 only) was conducted and re-evaluated. RESULTS: Stage 1 showed adequate scale performance for the MSIS-29 except for item misfit (6 Physical items; 2 Psychological items), suggesting more than two clinical conceptsperformed psychometrically well except for disordered thresholds (2/12), item misfit (3/12) and mis-targeting (person location range: -5.01 to 5.77; item location range: -2.99 to 4.10). For stage 2, two MSWS-12 items were rescored. The revised MSWS-12 showed improved scale performance (i.e., response categories and item fit), but not targeting. The MSIS-29 was re-categorized into three conceptually clearer sub-scales: ‘Symptoms’; ‘Psychological’; ‘Limitations’. The revised MSIS-29 scoring structure improved targeting and some item misfit (person location range; item location range; number of items misfitting): ‘Symptoms’ (-4.75 to 4.56; -3.38 to 2.17; 3/14); ‘Psychological’ (-4.20 to 4.27; -2.53 to 2.65; 1/5); ‘Limitations’ (-4.50 to 4.55; -2.75 to 2.69; 3/10). CONCLUSIONS: Findings from the post-hoc analyses of the proposed revised MSIS-29 and MSWS-12 provide an initial evidence-base for the enhancement of their measurement performance in patients with SPMS. Additional research is needed to determine the extent of improved scale-to-sample targeting and interpretability of the impact of MS.