OBJECTIVES: To compare the responsiveness of the Multiple Sclerosis Impact Scale (MSIS-29) with other self report scales in three multiple sclerosis (MS) samples using a range of methods. To estimate the impact on clinical trials of differing scale responsiveness. METHODS: We studied three discrete MS samples: consecutive admissions for rehabilitation; consecutive admissions for steroid treatment of relapses; and a cohort with primary progressive MS (PPMS). All patients completed four scales at two time points: MSIS-29; Short Form 36 (SF-36); Functional Assessment of MS (FAMS); and General Health Questionnaire (GHQ-12). We determined: (1) the responsiveness of each scale in each sample (effect sizes): (2) the relative responsiveness of competing scales within each sample (relative efficiency): (3) the differential responsiveness of competing scales across the three samples (relative precision); and (4) the implications for clinical trials (samples size estimates scales to produce the same effect size). RESULTS: We studied 245 people (64 rehabilitation; 77 steroids; 104 PPMS). The most responsive physical and psychological scales in both rehabilitation and steroids samples were the MSIS-29 physical scale and the GHQ-12. However, the relative ability of different scales to detect change in the two samples was variable. Differing responsiveness implied more than a twofold impact on sample size estimates. CONCLUSIONS: The MSIS-29 was the most responsive physical and second most responsive psychological scale. Scale responsiveness differs notably within and across samples, which affects sample size calculations. Results of clinical trials are scale dependent.