In the 2-year, phase 3 CARE-MS II study (NCT00548405), alemtuzumab demonstrated superior clinical and patient-reported outcomes (PROs) over subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis patients who had inadequate efficacy response to prior therapy. To further evaluate the relationship between PROs and disability, Short-Form 36-Item (SF-36) survey physical component summary (PCS) and mental component summary (MCS), and Functional Assessment of Multiple Sclerosis (FAMS) scores were analysed against Expanded Disability Status Scale (EDSS) outcomes, adjusted for baseline characteristics and randomisation arm. A 1.0-point difference in baseline EDSS score was associated with 2.0-point PCS, 0.8-point MCS, and 4.0-point FAMS worsening over 12 months (all P<0.001). A 1.0-point annualised EDSS score worsening corresponded to a 2.2-point PCS, 1.6-point MCS, and 6.0-point FAMS worsening (all P<0.001). For baseline EDSS score <4.0, 1.0-point annualised worsening was associated with 7.2-point FAMS and 2.0-point MCS worsening (both P<0.001). For baseline EDSS score ≥4.0, 1.0-point worsening corresponded to worsening on FAMS (2.4 points; P=0.04), but not MCS (P=0.82). Given that a half-point EDSS change is considered the minimum reliably measurable clinical difference, a 1.0-point change in SF-36 PCS and MCS or 3.0-point change in FAMS may represent a minimum important difference in PRO for multiple sclerosis patients.