The rationale for monitoring platelet inhibition by thienopyridines for the identification of patients at risk for future recurrent arterial thrombosis or ischemic events is intensively discussed, as well as which monitoring systems are appropriate, robust and reliable. Flow cytometric measurement of phosphorylated VASP (vasodilator-stimulated phosphoprotein), expressed as platelet reactivity index (PRI), is presently "the gold standard method" for evaluating P2Y(12) receptor inhibition. The PFA-100 system, a commercially available and clinically widely used platelet test system, is based on a different principle, not that of VASP phosphorylation. The aim of the present study was to compare the two methods and evaluate whether the conventional PFA-100 collagen/ADP cartridge could be pharmacologically improved to enable its routine clinical use for detection of platelet P2Y(12) receptor inhibition. The effects of increasing concentrations of the competitive P2Y(12) receptor antagonist cangrelor (AR-C69931MX) and the time-dependent effects of a single oral loading dose of clopidogrel (600 mg) were analysed with human whole blood. P2Y(12) receptor inhibition was measured by the VASP/PRI assay and the PFA-100 collagen/ADP cartridge system, with and without preincubation with the prostacyclin analog iloprost (Ilomedin). In vitro addition of iloprost (0.5 nM) enabled PFA-100 collagen/ADP cartridge system detection of P2Y(12) receptor inhibition in whole blood by cangrelor in vitro or by clopidogrel treatment of volunteers. The addition of a prostacyclin analog facilitates PFA-100 collagen/ADP system detection of P2Y(12) receptor inhibition, achieving a sensitivity similar to that of the VASP/PRI reference method. Future studies should now evaluate whether this modified PFA-100 system, like the VASP assay, is a reliable test system for monitoring P2Y(12) receptor inhibition under clinical conditions.