Previous work from this laboratory indicates a role for the complement component C5 in neuroprotection against excitotoxicity. In the present study, we tested the hypothesis that the C5-derived anaphylatoxin C5a protects against kainic acid (KA)-induced neurodegeneration and investigated the mechanism of C5a neuronal activity in vitro. Brain intraventricular infusion of KA into adult mice caused neuronal morphological features of apoptosis in the pyramidal layer of the hippocampal formation as indicated by counts of neurons with pyknotic/condensed nuclei associated with cytoplasmic eosinophilia. Co-intraventricular infusion of human recombinant C5a with KA resulted in a marked reduction of morphological features of apoptotic neuronal death. In vitro studies confirmed C5a neuroprotection: treatment of primary murine corticohippocampal neurons with human or mouse recombinant C5a reduced glutamate neurotoxicity, as measured by trypan blue exclusion assay. This protection concurred with inhibition of glutamate-mediated induction of the caspase-3-related cysteine protease and coincided with marked reduction of neurons with morphological features of apoptosis, as found in vivo. Our studies indicate that C5a may inhibit glutamate-mediated neuronal death through partial inhibition of caspase-3 activity. These findings suggest a novel noninflammatory role for C5a in modulating neuronal responses to excitotoxins.