Background: Physicians must weigh the benefits against the risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab, especially beyond 2 years. However, disability progression associated with switching therapies versus continuing natalizumab therapy after 2 years has not been fully evaluated. Methods: In this retrospective analysis using the NARCOMS Registry, disability progression (Patient-Determined Disease Steps [PDDS] scale) and physical health-related quality of life (HRQOL) worsening (12-item Short Form Health Status Survey Physical Component Score [SF-12 PCS]) were compared between participants switching to fingolimod (n = 50) or interferon beta (IFNβ)/glatiramer acetate (GA) (n = 71) therapy and those continuing natalizumab (n = 406) after 2 years or more of treatment (median follow-up: natalizumab, 4 years; fingolimod, 4.5 years; IFNβ/GA, 5 years). Results: Participants continuing to take natalizumab had less disability progression (mean PDDS change: natalizumab, 0.3; fingolimod, 0.6; IFNβ/GA, 0.7; P = .0036), were less likely to report disability progression (proportion with PDDS increase: natalizumab, 31%; fingolimod, 46%; IFNβ/GA, 42%; P = .0296), and had less worsening in physical HRQOL (mean SF-12 PCS change: natalizumab, -1.4; fingolimod, -2.8; IFNβ/GA, -4.6; P = .0476) than those switching treatment. Conclusions: Although all medication groups exhibited some level of worsening, switching from natalizumab treatment after 2 years was associated with increased disability progression and worsening physical HRQOL. The risk of disability progression from disease activity and the risk of PML should be considered when making natalizumab treatment decisions.