Complement is implicated in the pathogenesis of inflammatory disorders of the central nervous system (CNS), like multiple sclerosis, Alzheimer's disease, and trauma. The anaphylatoxins C3a and C5a are thought to be the major contributors to complement-mediated inflammation in the CNS, likely mediating their effects via their ability to attract and activate leukocytes and common capacity to augment inflammation. For example, in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, CNS-specific expression of C3a in C3a/GFAP transgenic mice renders them prone to massive cellular infiltration of the CNS and increases their mortality. In contrast, other studies have suggested that C3a can function in an anti-inflammatory fashion in the CNS, by inducing neurotrophin production and preventing NMDA-mediated neurotoxicity. To further investigate the seemingly paradoxical role of C3a in acute inflammation of the brain, we studied the pathogenesis of endotoxin shock in C3a/GFAP transgenic, C3a receptor-deficient (C3aR -/-) and C3a/GFAP × C3aR-/- mutant mice. Here we report that C3a/GFAP mice were significantly more resistant to endotoxin-induced lethality than wild-type and C3aR-/- mice. Surprisingly, C3a/GFAP × C3aR-/- hybrids were also significantly protected, indicating that C3a exerts its protective anti-inflammatory effect either directly or via an as yet unidentified non-canonical C3aR. © 2005 Elsevier Ireland Ltd. All rights reserved.