Adjunctive pharmacotherapy for stabilizing patients with acute coronary syndrome/non-ST-segment elevation myocardial infarction (ACS/NSTEMI) and for subsequent percutaneous coronary intervention (PCI) includes a combination of anticoagulant and antiplatelet agents. However, all anticoagulants have been shown to paradoxically activate platelets and induce other prothrombotic activities, increase bleeding, and/or cause thrombocytopenia. A single-center experience of 1,400 consecutive patients presenting with ACS/NSTEMI managed using decreased-dose anticoagulation (enoxaparin) and dual-antiplatelet therapy (aspirin and clopidogrel) followed by triple-antiplatelet therapy (aspirin, clopidogrel, and eptifibatide) alone, without additional anticoagulation, during subsequent PCI was retrospectively analyzed. Patients received a median of 3 doses of enoxaparin at a mean dose of 0.51 mg/kg. The final dose was administered 10.8 hours (mean) before PCI. Medical management "failed" in 8 patients (0.6%), and each required emergency PCI. The overall technical success rate was 99.8%. One major adverse clinical event (0.1%) occurred within 24 hours after PCI. Non-Q-wave myocardial infarction occurred in 1.8% of patients, major and minor bleeding complications, in 0.1% and 2.1%, respectively, and thrombocytopenia in 1.3%. Five additional major adverse clinical events (0.4%) occurred within 30 days after PCI, none involving target vessel thrombosis. In conclusion, for patients with ACS/NSTEMI, reduced-dose enoxaparin combined with dual-antiplatelet therapy followed by triple-antiplatelet therapy alone (without additional anticoagulation) during subsequent PCI appears safe and may prove efficacious.