Guinea pig (gp) platelets react to nanomolar doses of the complement-derived anaphylatoxin C5a with a shape change, aggregation and release of biogenic amines and nucleotides from their granules. We have investigated the specific receptor for C5a on gp platelets which mediates these biological effects. Competitive binding studies with 125I-labeled guinea pig C5a 125I-gpC5a) revealed approx. 4000 binding sites/cell with Kd = 6 x 10-9 M. The more than 60-fold higher biological activity (ATP-release from gp platelets) of gpC5a versus recombinant human C5a (rhuC5a) and the different binding behavior of gpC5a and rhuC5a point to a species restriction in the gp platelet system. Cross-linking of 125I-gpC5a to gp platelets (250 μM DSS) and analysis by SDS-PAGE under reducing conditions resulted in labeling of a single band with a molecular mass of 32 kDa (ligand-receptor complex). Because of these characteristics, the C5a receptor on gp platelets clearly differs from all previously described C5a receptors.