PURPOSE: COVID-19 patients in intensive care units (ICUs) requiring invasive mechanical ventilation (IMV) have few available treatment options. PANAMO, a multicenter, double-blind, randomized, placebo-controlled phase 3 study of vilobelimab, which blocks the inflammatory process caused by complement component 5a, demonstrated a significant mortality benefit at 28 and 60 days in these patients. A cost-effectiveness analysis was conducted to assess the incremental cost per quality-adjusted life-year (QALY). METHODS: A Markov model was used to estimate QALYs and the incremental cost-effectiveness ratio (ICER) of vilobelimab plus standard of care (SOC) versus SOC alone. The model simulated progression from severe COVID-19 to survival or death over a lifetime horizon. Outcomes data (COVID-19 all-cause mortality and renal replacement therapy) were incorporated from the PANAMO trial. COVID-19 mortality estimates were based on Centers for Disease Control and Prevention age-specific survival data. Utility values and hospital costs came from the literature. Vilobelimab cost was obtained from RED BOOK Online. RESULTS: For COVID-19 ICU patients, total costs of care were 03,414 (SOC) and 32,247 (SOC plus vilobelimab), respectively, resulting in an incremental cost of 8,833. SOC provided 6.70 QALYs versus 7.99 QALYs for vilobelimab, an additional 1.29 QALYs. The ICER for vilobelimab plus SOC versus SOC alone was 2,287/QALY. Probabilistic sensitivity analysis demonstrated the robustness of the cost-effectiveness result as vilobelimab plus SOC was favored at a willingness-to-pay threshold of 0,000 in over 81% of iterations. CONCLUSION: Vilobelimab provides a cost-effective option to treat ICU patients with severe COVID-19 receiving IMV compared to SOC, at well below the commonly accepted 0,000 US willingness-to-pay threshold.