Enoxaparin is increasingly used for the anticoagulation of patients undergoing percutaneous coronary intervention (PCI) alone or in conjunction with GpIIb/IIIa platelet antagonists. The purpose of this study was to evaluate a newly developed HEMONOX point-of-care test (POCT) for monitoring the effect of enoxaparin in the presence or absence of GpIIb/IIIa antagonists during PCI. Patients received two consecutive doses of enoxaparin (total 0.5 mg/kg) separated by a 5-minute interval either alone (n = 21) or in combination with a GpIIb/IIIa inhibitor following standard practice (n = 18). POCT HEMONOX, traditional coagulation tests, and plasma anti-Xa chromogenic activity assay were performed at baseline and post bolus. HEMONOX clotting time (CT) at baseline was identical in the enoxaparin (69.0 ± 8.0 seconds) and enoxaparin/GpIIb/IIIa (71.0 ± 8.0 seconds) treatment groups. HEMONOX CT achieved peak value at 10 minutes post initial dose (P < 0.0001) and then decreased at sheath removal (60 minutes post bolus; P = 0.001) in the two groups. HEMONOX peak response varied among patients, ranging from 130 to 431 (enoxaparin) and 104 to 386 (enoxaparin/GpIIb/IIIa) seconds, which corresponded to therapeutic anti-Xa levels of 0.69-1.14 and 0.61-1.10 U/mL, respectively. Mean HEMONOX CT was reduced 50 seconds in the presence of GpIIb/IIIa antagonists, which was associated with a reduction of anti-Xa activity (P = 0.038) but remained within therapeutic range. GpIIb/IIIa treatment did not alter the correlation between HEMONOX CT and anti-Xa activity levels (r = 0.85 vs 0.84); eptifibatide and abciximab yielded the best correlation (r > 0.90). HEMONOX was the most sensitive monitoring POCT during PCI.