In this proof-of-concept phase II trial, complement C5 inhibition with zilucoplan led to numerically relevant respiratory and clinical improvements in hypoxemic COVID-19 patients with systemic inflammation, associated with a drop in sC5b-9 and IL-8 concentration, thus indicating engagement of zilucoplan on its target protein in this population with high circulating C5 levels. Here, C5 is linked to COVID-19.