Thromboxane (Tx) A₂ is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA₂ formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI₂) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI₂receptor (IP) but are depressed in mice genetically deficient in the TxA₂ receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI₂ modulates platelet-vascular interactions in vivo and specifically limits the response to TxA₂. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI₂ but not TxA₂.