Summary. Background: Platelet ADP receptor P2Y12 is well studied and recognized as a key player in platelet activation, hemostasis and thrombosis. However, the role of P2Y12 in platelet apoptosis remains unknown. Objectives: To evaluate the role of the P2Y12 receptor in platelet apoptosis. Methods: We used flow cytometry and Western blotting to assess apoptotic events in platelets treated with ABT-737 or ABT-263, and stored at 37 °C, combined with P2Y12 receptor antagonists or P2Y12-deficient mice. Results: P2Y12 activation attenuated apoptosis induced by ABT-737 in human and mouse platelets in vitro, evidenced by reduced phosphatidylserine (PS) exposure, diminished depolarization of mitochondrial inner transmembrane potential (ΔΨm) and decreased caspase-3 activation. Through increasing the phosphorylation level of Akt and Bad, and changing the interaction between different Bcl-2 family proteins, P2Y12 activation inactivated Bak/Bax. This antiapoptotic effect could be abolished by P2Y12 antagonism or PI3K inhibition. We also observed the antiapoptotic effect of P2Y12 activation in platelets stored at 37 °C. P2Y12 activation improved the impaired activation responses of apoptotic platelets stressed by ABT-737. In platelets from mice dosed with ABT-263 in vivo, clopidogrel or deficiency of P2Y12 receptor enhanced apoptosis along with increased Bak/Bax activation. Conclusions: This study demonstrates that P2Y12 activation protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation, which may be physiologically important to counter the proapoptotic challenge. Our findings that P2Y12 blockade exaggerates platelet apoptosis induced by ABT-263 (Navitoclax) also imply a novel drug interaction of ABT-263 and P2Y12 antagonists.