Background: In RRMS patients with inadequate response to prior therapy, 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved outcomes versus SC IFNB-1a over 2 years (CARE-MS II [NCT00548405]). Efficacy remained durable in a 4-year extension (NCT00930553); patients could receive as-needed alemtuzumab retreatment (≥12 months apart) for disease activity, or another disease-modifying therapy (DMT). Through Year 6, 88% remained on study; 50% received neither alemtuzumab retreatment nor another DMT; 16% received ≥4 courses; 3% received ≥5 courses. We evaluated Course 4 (C4) efficacy in patients receiving ≥4 courses. Methods: Annualized relapse rate (ARR); improved/stable Expanded Disability Status Scale (EDSS) score (versus baseline); 6-month confirmed disability improvement (CDI). 11% of patients met inclusion criteria: ≥4 courses within 60 months of baseline; no DMT. Those receiving C5 were censored at that time. Results: ARR decreased after C4 (12 months pre-C4 [-12M]: 0.75; 12 months post-C4 [+12M]: 0.19; P<0.0001), remaining low (0.23) at Year 3 post-C4. More patients had stable/improved EDSS scores +12M (67.5%) versus at C4 administration (53.5%). Percentage with CDI increased post-C4 (-12M: 10.0%; +12M: 26.7%). Conclusions: C4 reduced relapses and stabilized/improved disability in patients with disease activity after initial treatment (C1, C2) plus one additional course (C3).