A single component in the plasma membrane of human polymorphonuclear leukocytes (hPMN) has been identified as the binding site for C5a. Labelled human C5a can be cross-linked to a 48,000-Mr membrane component on the hPMN surface by using the bifunctional reagent ethylene glycol bis(succinimidyl succinate). The membrane component is believed to be the C5a receptor or the binding subunit of a C5a receptor complex. Our ligand-uptake data indicate that the hPMN has high-affinity binding sites for C5a with a Kd of the order of 1-2 nM and an estimated 50,000-113,000 binding sites/cell. Preliminary binding studies of C3a and C5a to rat peritoneal mast cells indicate that non-specific uptake by these cells is so great that it obscures characterization of specific receptor interactions. Data recently reported [Gervasoni, Conrad, Hugli, Schwartz & Ruddy (1986) J. Immunol. 136, 285-292] suggest that non-specific binding of C3a to mast cells is caused by electrostatic interactions between the cationic ligand and anionic heparin-proteoglycan on the cell surface, with an additional complication of the bound ligand undergoing proteolytic degradation. It is therefore proposed that synthetic analogue peptides designed to minimize non-specific interactions with the cell will be useful tools for demonstrating anaphylatoxin receptors on mast cells and may prove essential for receptor isolation.