Polymorphisms in alphaIIbbeta3 are important genetic factors that alter platelet biology and have been associated with susceptibility to thromboembolic disorders. To define the molecular mechanisms that lead to variance in thrombotic diathesis dictated by the beta3 polymorphism, we examined regulation of intracellular signaling by alphaIIbbeta3, and studied the effects of a common beta subunit PlA2 polymorphism. We found that PP2A regulates alphaIIbbeta3 control of the ERK signaling in a polymorphism specific fashion. In CHO cells, exogenous expression of alphaIIbbeta3 reduced ATP-stimulated ERK phosphorylation and more so for PlA2 than PlA1. Interestingly, reduced level of ERK phosphorylation correlated with an increase in PP2A activity, with higher activity associated with PlA2 than PlA1. We tested the effect of PP2A on alphaIIbbeta3-dependent adhesion, and found that PP2A overexpression increased cell adhesion, while phosphatase inhibitors decreased cell adhesion. We propose that PlA2 alters cell signaling at least in part by increasing beta3-associated PP2A activity.