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Hyperinflammation, including complement over\u2010activation, has a pivotal role in severe COVID\u201019 pathobiology, stimulating the inflammatory response, causing microangiopathy, platelet\u2013neutrophil activation, and hypercoagulability. SARS\u2010CoV\u20102 can directly activate the complement system by the classic, alternative, and lectin pathways, and infected cells can produce intracellular complement (the complesome). COVID\u201019 severity appears to be associated with the degree of complement activation, and it has been hypothesized that patients with COVID\u201019 may benefit from therapeutic complement inhibition. Different complement cascade molecules may be targeted with potential advantages and disadvantages. Which target(s) is the most effective and when is the best timing for intervention remain open questions. Early phase I and phase II clinical trials have shown promising but conflicting results, warranting phase III controlled randomized trials. Upstream complement inhibition appears to better and more effectively block hyperinflammation with potential clinical significance. 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