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Complement inhibition is a highly effective strategy for preventing relapse and disability accumulation in neuromyelitis optica spectrum disorder (NMOSD). Invasive infection with Neisseria meningitidis, the principal risk of complement inhibition, is largely mitigated by adequate vaccination. However, vaccination in the context of treatment sequencing from other immunosuppressive therapies, in particular rituximab, presents unique challenges. We present a 17-year-old woman with a severe NMOSD relapse despite B-cell depletion, who subsequently developed meningococcal sepsis after treatment with ravulizumab, despite prior vaccination; and we propose strategies to manage risk in this patient population.