Shear-induced platelet activation may cause life-threatening thrombosis, particularly in patients with mechanical support devices or coronary atherosclerosis. The majority of present anti-platelet agents target or interfere with biochemical, rather than physical mechanisms of platelet activation. Less data and understanding exists with regard to pharmacologic modulation of shear-mediated platelet activation. In this work, we hypothesized that modulating cell membrane properties, via alteration of membrane composition through addition of exogenous lipid moieties, would alter platelet responsiveness to shear. Here we tested fatty acids, lecithin and cholesterol as additive lipid compounds. We demonstrated that incorporation of fatty acids (DHA/EPA) or lecithin into the platelet membrane triggered enhanced sensitivity of platelets to shear-mediated activation. On the other hand, cholesterol incorporation provides significant protection, limiting the effect of shear on platelet activation. These findings provide valuable insight for the development of therapeutic strategies that can modulate shear-mediated platelet activation.