αIIbβ3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a “β3(Δ760-762)” knockin mouse was generated that lacked the 3 C-terminal β3 residues (arginine-glycine-threonine [RGT]) necessary for αIIbβ3 interaction with c-Src, but retained β3 residues necessary for talin-dependent fibrinogen binding. β3(Δ760-762) mice were compared with wild-type β3^+/+ littermates, β3^+/− heterozygotes, and knockin mice where β3 RGT was replaced by β1 C-terminal cysteine-glycine-lysine (EGK) to potentially enable signaling by Src kinases other than c-Src. Whereas β3^+/+, β3^+/− and β3/β1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, β3(Δ760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including β3 (Tyr⁷⁴⁷). Unlike control mice, β3(Δ760-762) mice were protected from carotid artery thrombosis after vessel injury with FeCl₃. Some β3(Δ760-762) mice exhibited prolonged tail bleeding times; however, none demonstrated spontaneous bleeding, excess bleeding after surgery, fecal blood loss, or anemia. Fibrinogen binding to β3(Δ760-762) platelets was normal in response to saturating concentrations of protease-activated receptor 4 or glycoprotein VI agonists, but responses to adenosine diphosphate were impaired. Thus, deletion of β3 RGT disrupts c-Src–mediated αIIbβ3 signaling and confers protection from arterial thrombosis. Consequently, targeting αIIbβ3 signaling may represent a feasible antithrombotic strategy.