Overall, these data indicate that endothelial dysfunction induced by SARS-CoV-2-derived S1 protein triggers exuberant complement deposition on activated microvascular endothelial cells and that the anaphylatoxins C3a and, to a lesser extent, C5a, further amplify the complex process of complement activation that fuels inflammation in response to S1. Here, C5 is linked to endothelial dysfunction.