The fibrin(ogen) receptor, integrin αIIbβ3, has a well-established role in platelet spreading, aggregation and clot retraction. How αIIbβ3 contributes to platelet-dependent coagulation is less well resolved. Here, we demonstrate that the potent suppressing effect of clinically used αIIbβ3 blockers on tissue factor-induced thrombin generation is linked to diminished platelet Ca2+ responses and phosphatidylserine (PS) exposure. The same blockers suppress these responses in platelets stimulated with collagen and thrombin receptor agonists, whereas added fibrinogen potentiates these responses. In platelets spreading on fibrinogen, outside-in αIIbβ3 signaling similarly enhances thrombin-induced Ca2+ rises and PS exposure. These responses are reduced in αIIbβ3-deficient platelets from patients with Glanzmann’s thrombasthenia. Furthermore, the contribution of αIIbβ3 to tissue factor-induced platelet Ca2+ rises, PS exposure and thrombin generation in plasma are fully dependent on Syk kinase activity. Tyrosine phosphorylation analysis confirms a key role of Syk activation, which is largely but not exclusively dependent on αIIbβ3 activation. It is concluded that the majority of tissue factor-induced procoagulant activity of platelets relies on Syk activation and ensuing Ca2+ signal generation, and furthermore that a considerable part of Syk activation relies on αIIbβ3 signaling. These results hence point to a novel role of Syk in integrin-dependent thrombin generation.