Selected aspirin treated patients may exhibit high platelet reactivity to agonists other than arachidonic acid. This study aimed to determine whether the VerifyNow identifies generalized high platelet reactivity supported by correlations with other established methods that stimulate platelets with various agonists. Stable outpatients with coronary artery disease (n = 110) were treated with aspirin in a two 3 x 3 Latin square design (81, 162 and 325 mg/day for 4 weeks each). VerifyNow (arachidonic acid (AA) cartridge); light transmittance aggregometry; thrombelastography; PFA-100; flow cytometry; PlateletWorks; and urinary 11- dehydro thromboxane levels were measured. Multianalyte profiling measured fibrinogen and von Willebrand factor (vWF). Patients with >or=550 ARU by VerifyNow had increased 5 mM AA-, 5 microM ADP-, and 2 microg/mL collagen-induced platelet aggregation compared to patients with <550 ARU (p <or= 0.001). The highest ADP- and collagen-induced aggregation was present in the upper quartile by VerifyNow (p < 0.05). Fibrinogen or vWF levels did not differ between VerifyNow quartiles. Patients with high platelet reactivity to arachidonic acid identified by VerifyNow also exhibit increased reactivity to other important platelet agonists that is independent of fibrinogen and vWF levels. These data suggest that VerifyNow may identify a generalized high platelet reactivity phenotype.