Modern antithrombotic strategies for patients undergoing percutaneous coronary interventions (PCIs) must take into account the risk of ischemic and hemorrhagic complications. Bivalirudin decreases the risk of hemorrhagic complications after PCI; however, concerns have been raised about its efficacy in preventing ischemic complications. We evaluated the effectiveness of a prolonged intra- and postprocedural bivalirudin infusion versus a standard regimen in preventing PCI-related myocardial damage. One hundred seventy-eight consecutive patients with stable or unstable angina and complex coronary anatomy were enrolled in this single-center, randomized, single-blinded study. Patients were randomized to bolus plus bivalirudin infusion during PCI (n = 90) or bolus plus bivalirudin infusion during and after PCI (4 hours, n = 88). The primary end point was incidence of periprocedural myocardial damage (creatine kinase-MB increase >or=3 times upper limit of normal). Secondary end points were 30-day and 6-month major adverse cardiovascular events (death, new Q-wave myocardial infarction, target vessel revascularization) and in-hospital bleeding (major/minor). The 2 groups did not differ significantly in baseline and procedural characteristics. The primary end point of the study was significantly less frequent in the prolonged infusion group (6.8% vs 16.7%, p = 0.041). No significant differences for secondary end points were observed. In conclusion, in patients undergoing complex PCI, a prolonged bivalirudin infusion after PCI compared to an intraprocedural-only regimen significantly decreased the incidence of periprocedural myocardial damage.