Neutrophils are involved in numerous pathologies and are considered to be major contributors to the establishment of cutaneous loxoscelism after envenomation by the Loxosceles spider. Neutrophils are attracted to the site of envenomation by locally generated C5a and contribute to the tissue destruction. We have investigated the effects of this spider venom on the receptor for C5a: C5aR/CD88, a seven transmembrane G-protein coupled receptor. We show here that the Loxosceles venom induces the cleavage of the C5aR at two sites, resulting in the release of the extracellular N-terminus, while retaining part of the transmembrane regions. Using specific inhibitors, it was shown that the cleavage was induced by activation of an endogenous metalloprotease of the adamalysin (ADAM) family, which was activated by the sphingomyelinase D in the venom. Although it resulted in the near complete loss of the N-terminus, C5a was still able to induce a small increase in intracellular calcium and increase secretion of IL-8. The cleavage of the C5aR may well be a protective response after envenomation, rather than contributing to the pathology of Loxosceles envenomation and may represent a general mechanism for how the body protects itself against excess C5a generation in pathological circumstances such as sepsis.