Advances in percutaneous coronary intervention (PCI) during the past decade have led to more widespread use of these procedures in older and sicker patients. Refinement of periprocedural antithrombotic therapy has played a particularly important role in reducing ischemic complications to very low levels in routine practice. Although the use of more powerful antiplatelet agents has been associated with increased risk of bleeding (especially among the elderly and patients with serious comorbidities), such complications have traditionally been viewed as benign in nature. Recent studies, however, have identified major bleeding after PCI as an important predictor of increased mortality. Whether this relationship between bleeding and risk of death is cause-and-effect, or merely an association based on shared risk factors, remains unclear. In this review, we examine the basis for a possible causal link between post-PCI bleeding and subsequent mortality. Possible mechanisms underpinning such a link are discussed, including a potential adverse role for blood transfusion in this setting. A framework for further clinical evaluation of this issue is presented.