Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Whilst these anti-drug responses have been reported to be of no significance, we hypothesised that they will affect the depleting-capacity and treatment-response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population-level there was lack of influence of "ever-positive" alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and side-effects during the two year trial. This was not surprising as no one prior to first-infusion, and only 0.6% of people prior to the second-infusion had pre-infusion, neutralizing antibodies (Nabs). However, at the individual-level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, suggests that problems may occur in people requiring addition alemtuzumab-cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Thus, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete-poorly, probably due to biological-response variation and NAbs and this may lead to treatment failure. Monitoring depletion following infusion and assessment of neutralizing response prior to re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure. This article is protected by copyright. All rights reserved.