Increasing evidence suggests that strong P2Y12 receptor blockade may attenuate both ADP- and thromboxane (TX) A2-dependent pathways of platelet aggregation. To explore this, we compared the potency of two structurally distinct P2Y12 receptor antagonists for (i) inhibition of ADP-dependent aggregation, and (ii) inhibition of TXA2-dependent aggregation and TXA2-synthesis. Platelet-rich plasma from healthy human volunteers was treated with (i) ticagrelor (0.1–10 μM), (ii) prasugrel-active-metabolite (PAM; 0.1–10 μM) or (iii) vehicle. Aggregations to ADP, the TXA2 mimetic U46619 and arachidonic acid (AA) were recorded using 96-well plate light transmission aggregometry. TXA2 synthesis was measured by ELISA for TXB2. Ticagrelor and PAM produced concentration-dependent inhibitions of aggregation to ADP. Ticagrelor was more potent than PAM (−logIC50 against 20 μM ADP: 6.5±0.1 vs 5.6±0.1; p<0.01). As has been reported previously, the potency of ticagrelor, but not PAM, was greater at lower agonist concentration (eg, −logIC50 against 2.5 μM ADP: 7.1±0.3). Both drugs inhibited U46619-induced aggregation (logIC50 against 3 μM U46619, 6.5±0.3 and 5.6±0.1, respectively for ticagrelor and PAM), AA-induced aggregation (−logIC50 against 1 mM AA, 6.8±0.1 and 5.9±0.1) and AA-induced TXA2 formation −logIC50 against 1 mM AA, 6.9±0.9 and 5.9±0.3) with similar potencies as against ADP. P2Y12 antagonists inhibit TXA2 receptor (TP)-dependent platelet aggregation and TXA2 synthesis with similar potencies to those inhibiting ADP-induced aggregation. This is consistent with the idea that the ADP-P2Y12 interaction is crucial in supporting the activation mechanisms downstream of the TXA2 receptor, TP, and those driving TXA2 synthesis. These results question the necessity of anti-thrombotic aspirin therapy when used in combination with strong P2Y12 inhibition.