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Using peptides that represent linear regions of the powerful complement activation product, C5a, or loops that connect the four α helices of C5a, we have defined the ability of these peptides to reduce binding of 125 I-C5a to human neutrophils, inhibit chemotactic responses of neutrophils to C5a, and reduce H 2 O 2 production in neutrophils stimulated with PMA. The data have defined likely sites of interaction of C5a with C5aR. The peptides had no functional activity per se on neutrophils and did not interfere with neutrophil responses to the unrelated chemotactic peptide, N-formyl-Met-Leu-Phe. Although previous data have suggested that there are two separate sites on C5a reactive with C5aR, the current data suggest that C5a interacts with C5aR in a manner that engages three discontinuous regions of C5a.