PMX-53, a macrocyclic complement 5a (C5a) peptidomimetic and C5a receptor antagonist (IC50 = 0.3 µM), effectively inhibits the C5a-induced secretion of myeloperoxidase (MPO) in isolated human polymorphonuclear leukocytes (PMNs). Administered orally at 10 mg/kg, PMX-53 mitigates vascular leakage, PMN infiltration, and the production of TNF-α and IL-6 in a rat peritoneal Arthus reaction model. Additionally, in a 3-nitropropionic acid (3-NP)-induced Huntington’s disease rat model, it alleviates body weight loss, anorexia, and striatal degeneration. Furthermore, at a dose of 3 mg/kg, PMX-53 decreases atherosclerotic lesion size and lipid content in ApoE-/- mice.