This study evaluated the mechanism of epinephrine potentiation of platelet secretion induced by thromboxane A₂ (TXA₂). Dog platelets that do not secrete in response to TXA₂ alone (TXA₂) were compared with dog platelets that do secrete (TXA₂+) and with human platelets. TXA₂ platelets had impaired TXA₂ receptor (TP receptor)-G protein coupling, indicated by 1) impaired stimulated GTPase activity, 2) elevated basal guanosine 5'-O-(3-thiotriphosphate) binding, and 3) elevated G_q palmitate turnover that was corrected by preexposure to epinephrine. Kinetic agonist binding studies revealed biphasic dog and human platelet TP receptor association and dissociation. TXA₂ and TP receptor-desensitized TXA₂+ dog and human platelets had altered ligand binding parameters compared with untreated TXA₂+ or human platelets. These parameters were reversed, along with impaired secretion, by epinephrine. Basal phosphorylation of TXA₂ platelet TP receptors was elevated 60% and was normalized by epinephrine. Epinephrine potentiates platelet secretion stimulated by TXA₂ by reducing basal TP receptor phosphorylation and facilitating TP receptor-G protein coupling in TXA₂ platelets and, probably, in normal platelets as well.