Percutaneous coronary intervention (PCI) of calcified coronary lesions has been associated with increased rates of adverse ischemic events. However, the potential association between the presence and severity of calcific deposits and bleeding complications has yet to be investigated. Data from 6,855 patients with non–ST-segment elevation acute coronary syndrome (NSTEACS) or ST-segment elevation myocardial infarction (STEMI) treated with PCI were pooled from 2 large-scale randomized controlled trials—Acute Catheterization and Urgent Intervention Triage Strategy and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction. Patients were stratified into 3 groups according the grade of target PCI lesion calcium (none to mild, moderate, and severe) as assessed by an independent angiographic core laboratory. Thirty-day bleeding event rates were assessed and compared among groups. In the total cohort undergoing PCI, none-to-mild target lesion calcium was found in 4,665 patients (68.1%), moderate target lesion calcium in 1,788 patients (26.1%), and severe target lesion calcium in 402 patients (5.9%). The 30-day rates of non–coronary artery bypass graft surgery major bleeding increased significantly with each degree of coronary calcium (none to mild = 5.9%, moderate = 7.2%, and severe = 11.2%, p = 0.0003). By multivariable analysis, presence of severe calcium was an independent predictor of non–coronary artery bypass graft major bleeding after PCI (hazard ratio 1.54, 95% confidence interval 1.09 to 2.17, p = 0.01). In conclusion, in patients undergoing PCI for non–ST-segment elevation acute coronary syndrome and ST-segment elevation myocardial infarction, target lesion coronary calcium was an independent predictor of major bleeding events. Further studies are needed to elucidate mechanisms underlying this finding and to optimize treatment of this high-risk population.