The role of the phospholipase C (PLC)γ2 isotype in platelet activation was evaluated by studying PLCγ2 −/− mice. These mice have a prolonged bleeding time but their platelets respond normally to non‐collagenous agonists. PLCγ2‐null platelets show residual aggregation response to collagen fibres (6% versus 74% for wild‐type) with minimal granule secretion and no shape change. A delayed shape change is observed at later aggregation times. Specific activation by glycoprotein (GP)VI agonists (convulxin, collagen‐related peptide and GPVI crosslinking) is, however, abolished. Antibodies against integrin α₂β₁ and GPVI each inhibit the residual collagen response, implying a role of α₂β₁ in platelet activation and a functional association with GPVI. These responses are also prevented by blocking integrin α_IIbβ₃ and phosphoinositide 3‐kinase, whereas aspirin treatment and ADP receptor blockade only inhibit shape change. These results provide evidence for a PLCγ2‐independent collagen activation pathway requiring cooperation between GPVI and α₂β₁ leading to α_IIbβ₃‐dependent aggregation and shape change by released ADP and thromboxane A₂.