Increasing evidence suggests that treatment with the low molecular weight heparin enoxaparin during percutaneous coronary intervention (PCI) is safe and effective. We evaluated the incidence and consequences of periprocedural macroscopic thrombus formation on PCI equipment following antithrombin therapy with enoxaparin. Between April 2003 and December 2004, all patients undergoing cardiac catheterization following antithrombin therapy with enoxaparin were evaluated. All patients had blood sampled at the onset of procedure for subsequent measurement of anti-factor-Xa levels. Of the 4,504 patients who underwent PCI during this period, in 122 (3%) the procedure was performed within 8 hr of treatment with subcutaneous enoxaparin and no additional unfractionated heparin (UFH) was used periprocedurally. Of these, macroscopic thrombus was observed on PCI equipment in 6 patients (5%) necessitating withdrawal of all catheters and wires. All patients had therapeutic anti-factor-Xa levels at the time of PCI, and had been treated with double antiplatelet therapy with aspirin and clopidogrel. No periprocedural thrombus was observed in 356 patients who were >12 hr of the last dose of enoxaparin and received UFH at the time of PCI. Following observation of thrombus, additional anticoagulation with UFH resulted in significant epistaxis in one patient. In another patient, the procedure was complicated by distal coronary embolization. Percutaneous coronary intervention following antithrombin therapy with enoxaparin is associated with a 5% incidence of macroscopic thrombus formation on PCI equipment. The necessity for subsequent exchange of all equipment and/or the need for additional anticoagulation may have disastrous consequences for the patient. Our findings suggest that the safety of antithrombin therapy with low molecular weight heparin during PCI requires further evaluation.