The clinical relevance of periprocedural myocardial injury related to percutaneous coronary intervention (PCI) remains controversial. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is a sensitive indicator of hemodynamic stress and when increased is associated with higher mortality in patients with acute and chronic ischemic heart disease. We measured the serum level of NT-pro-BNP using the Elecsys 2010 proBNP assay at baseline, 4 to 6 hours, and 12 to 24 hours in 747 patients undergoing elective or urgent PCI and enrolled in the JUMBO-TIMI 26 trial. Periprocedural myocardial infarction (MI) was independently adjudicated and required a new increase in creatine kinase-MB >3 times the upper limit of normal distinct from MI as the indication for PCI. Patients with procedural MI had significantly higher levels of NT-pro-BNP at 12 to 24 hours (405 vs 146 pg/ml, p <0.001). Moreover, the greater increase in NT-pro-BNP in patients with periprocedural MI was independent of each clinical and other procedural correlates of NT-pro-BNP after PCI (p <0.001). In addition, the magnitude of increase in NT-pro-BNP correlated strongly with extent of myocardial injury, including in patients with evidence of injury (creatine kinase-MB 1 to 3 times upper limit of normal) not meeting criteria for MI (p = 0.001) or low-level increase in troponin T (p = 0.001). In conclusion, periprocedural myocardial injury, even at low levels, during PCI is associated with increased hemodynamic stress as measured by increasing NT-pro-BNP. This finding supports the physiologic relevance of procedural MI and the continued effort to define therapies that decrease the risk of this complication.