BACKGROUND: The benefit:risk profile of bivalirudin versus heparin anticoagulation in patients with non–ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) is uncertain. Study-level meta-analyses lack granularity to provide conclusive answers. We sought to compare the outcomes of bivalirudin and heparin in patients with non–ST-segment–elevation myocardial infarction undergoing PCI. METHODS: We performed an individual patient data meta-analysis of patients with non–ST-segment–elevation myocardial infarction in all 5 trials that randomized ≥1000 patients with any myocardial infarction undergoing PCI to bivalirudin versus heparin (MATRIX, VALIDATE-SWEDEHEART, ISAR-REACT 4, ACUITY [Acute Catheterization and Urgent Intervention Triage Strategy], and BRIGHT). The primary effectiveness and safety end points were 30-day all-cause mortality and serious bleeding. RESULTS: A total of 12 155 patients were randomized: 6040 to bivalirudin (52.3% with a post-PCI bivalirudin infusion), and 6115 to heparin (53.2% with planned glycoprotein IIb/IIIa inhibitor use). Thirty-day mortality was not significantly different between bivalirudin and heparin (1.2% versus 1.1%; adjusted odds ratio, 1.24 [95% CI, 0.86–1.79]; P =0.25). Cardiac mortality, reinfarction, and stent thrombosis rates were also not significantly different. Bivalirudin reduced serious bleeding (both access site–related and non—access site–related) compared with heparin (3.3% versus 5.5%; adjusted odds ratio, 0.59; 95% CI, 0.48–0.72; P <0.0001). Outcomes were consistent regardless of use of a post-PCI bivalirudin infusion or routine lycoprotein IIb/IIIa inhibitor use with heparin and during 1-year follow-up. CONCLUSIONS: In patients with non–ST-segment–elevation myocardial infarction undergoing PCI, procedural anticoagulation with bivalirudin and heparin did not result in significantly different rates of mortality or ischemic events, including stent thrombosis and reinfarction. Bivalirudin reduced serious bleeding compared with heparin arising both from the access site and nonaccess sites.