OBJECTIVES: The psychometric properties of the Multiple Sclerosis Impact Scale (MSIS-29) have been well examined in community-based samples using cross-sectional data, but not yet in trial-based samples using longitudinal data. This analysis examined MSIS-29’s validity and responsiveness using longitudinal data from patients with relapsing-remitting multiple sclerosis (RRMS) enrolled in the SELECT trial of daclizumab HYP. METHODS: The MSIS-29 and EQ-5D tariff and visual analogue scale (VAS) were administered at baseline, 3, 6, and 12 months to 600 patients with RRMS who had mean age of 35.8 (SD=8.91) years and Expanded Disability Status Scale of 2.7 (SD=1.17) at baseline. The convergent and discriminant validity of MSIS-29 was assessed by examining the strength of correlations between the physical and psychological scores of the MSIS-29 and each of the five EQ-5D dimensions at all time points. MSIS-29 responsiveness was evaluated by examining the direction, magnitude, and pattern of change in MSIS-29 scores in three patient subgroups defined by achieving an established minimal important EQ-5D VAS change of 5.5 points at each time point from baseline (improved ≥5.5, -5.5 < stable <5.5, worsened ≤-5.5). RESULTS: As expected, the MSIS-29 physical scale was more highly correlated with the EQ-5D dimensions usual activities (r=0.66) and mobility (r=0.62) and least correlated with anxiety/depression (r=0.48). Conversely, the psychological scale was more highly correlated with the EQ-5D anxiety/depression (r=0.64) and least correlated with personal care (r=0.35) and mobility (r=0.42). The direction, magnitude, and pattern of change in the physical and psychological scores over time in each subgroup were consistent with expectations, showing insignificant change among stable patients, but significant change among those who improved or worsened.  CONCLUSIONS: The MSIS-29 is a valid and responsive measure among trial-based subjects. This analysis supports its use as a disease-specific measure of treatment effect on the physical and psychological well-being of MS patients.