In a large phase III study of patients with unstable angina treated with percutaneous transluminal coronary angioplasty (PTCA), the thrombin-specific anticoagulant bivalirudin produced relative risk reductions of 22% (p = 0.039) for ischemic complications and 62% (p < 0.001) for bleeding complications compared with heparin. Subsequent reports have shown that between-treatment differences favoring fewer complications with bivalirudin also extend to high-risk patients. Early heparinization promotes heparin resistance and decreases activated clotting time achieved during PTCA. These effects are relevant to patients with postinfarction angina, which is associated with a greater likelihood of early vessel closure and procedural failure. In 1006 patients with one or both of these risk factors, bivalirudin significantly reduced combined ischemic and bleeding complications compared with heparin (8.6% vs 18%, p < 0.001). Treatment separations favoring bivalirudin increased with risk, suggesting decreased heparin effectiveness in patients at heightened risk. Findings in three additional risk groups-women, the elderly, and patients not receiving glycoprotein IIb/IIIa inhibitors-also showed fewer complications with bivalirudin therapy. Preliminary data suggest that bivalirudin can be combined safely with glycoprotein IIb/Illa antagonists in percutaneous coronary intervention (PCI), including PTCA. An ongoing trial is aimed at determining the efficacy and safety of heparin with planned glycoprotein IIb/IIIa therapy versus bivalirudin with provisional glycoprotein IIb/IIIa therapy. The use of bivalirudin in patients with heparin-induced thrombocytopenia also is being evaluated after favorable findings in early compassionate-use studies. The fact that between-treatment differences favoring bivalirudin were especially outstanding among the high-risk patients considered in this review reinforces the impression that bivalirudin is a promising and unprecedented alternative to heparin in PCI.