Objective CHAMPION‐NMOSD (NCT04201262) is a phase 3, open‐label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti–aquaporin‐4 antibody–positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half‐life, enabling an extended dosing interval (8 vs 2 weeks). Methods The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION‐NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight‐based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on‐trial relapse. Results The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient‐years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient‐years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%–100.0%, p < 0.0001). Median (range) study period follow‐up time was 73.5 (11.0–117.7) weeks for ravulizumab. Most treatment‐emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. Interpretation Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053–1068