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Carbenicillin (carb) and penicillin G (pen) inhibit human platelet function in vivo and can cause a bleeding diathesis. Since the mechanism by which these drugs inhibit platelets is unknown, we investigated whether they might interfere with the binding of epinephrine, ADP, or ristocetin (von Willebrand factor) to the platelet surface in vitro. Pen (10 mM) or carb (20 mM) produced a 6-fold decrease in the affinity of receptors on intact platelets for both epinephrine and for the α-adrenergic antagonist, 3U-dihydroer-gocryptine (p < 0.001). Neither antibiotic changed the maximum number of α-adrenergic binding sites per platelet. Pen and carb at these concentrations completely inhibited 14C-serotonin release induced by 1 μM epinephrine and inhibited primary platelet aggregation by 1 μM. Similarly, these antibiotics inhibited aggregation and serotonin release induced by 1 μM ADP and inhibited the covalent binding of an ADP analogue (5'FSO2BZAdo) to its specific binding protein in platelet membranes. Moreover, pen and carb inhibited competitively the agglutination of platelets by ristocetin. Thus, carbenicillin and penicillin G decrease the affinity of a number of distinct platelet receptors for their specific agonists, and this correlates with inhibition of platelet function induced by these agonists. Interaction of these antibiotics with the platelet surface membrane may account for their hemorrhagic as well as their anti-thrombotic activity.