Natalizumab, an alpha-4-integrin-targeting monoclonal antibody, is a high efficacy treatment option for relapsing-remitting multiple sclerosis (MS). A notable concern with natalizumab use is the increased risk of progressive multifocal leukoencephalopathy (PML) from John Cunningham virus (JCV) infection. JCV-antibody levels are used to monitor patients’ risk and guide treatment switching decisions. Claire Riley, MD, Columbia University Irving Medical Center, New York, NY, describes the established approach used in her clinic for safely transitioning patients with MS at risk of PML from natalizumab to ocrelizumab without allowing rebound disease activity. This interview took place during the ACTRIMS Forum 2021.