Glycoproteins GPVI and GPIb-IX-V stimulate robust tyrosine phosphorylation of Syk and PLCγ2 (phospholipase Cγ2) in washed platelets, but only the former stimulates pronounced activation of phospholipase. Using phospho-specific antibodies, we demonstrate that GPVI, but not GPIb-IX-V, stimulates significant tyrosine phosphorylation of Syk at the autophosphorylation site pY525/526, a marker of Syk activity. In addition, GPVI stimulates tyrosine phosphorylation of PLCγ2 at Tyr⁷⁵³ and Tyr⁷⁵⁹, whereas GPIb-IX-V only induces significant phosphorylation at Tyr⁷⁵³. Both receptors stimulate tyrosine phosphorylation of Btk at the regulatory Tyr²²³ and Tyr⁵⁵¹. Syk and Btk phosphorylate peptides from PLCγ2 containing Tyr⁷⁵³ and Tyr⁷⁵⁹ respectively, suggesting that they may stimulate phosphorylation at these sites in phospholipase. Studies using PLCγ2-deficient platelets demonstrated that phospholipase is not required for the activation of integrin αIIbβ3 by GPIb-IX-V. Our results demonstrate fundamental differences between GPVI and GPIb-IX-V in the regulation of tyrosine phosphorylation of Syk and PLCγ2 consistent with the functional impairment of phospholipase in signalling by GPIb-IX-V.