Limited data are available regarding the predictors of periprocedural creatine kinase-MB (CK-MB) isoenzyme increase after elective percutaneous coronary intervention (PCI) in the stenting era. We explored the predictors of periprocedural CK-MB increase in 882 consecutive patients with normal preprocedural CK-MB who underwent 919 angiographically successful elective PCIs with (n = 814) or without (n = 105) stenting. Patients were categorized into 3 groups based on their peak CK-MB levels after PCI: (1) normal CK-MB (n = 761), (2) minor CK-MB increase (CK-MB 1 to 3 times normal, n = 112), and (3) major CK-MB increase (CK-MB >3 times normal, n = 46). By logistic regression analysis, independent predictors for minor CK-MB increase included thrombus (odds ratio [OR] 5.09, p = 0.001), platelet IIb/IIIa antagonist use (OR 0.53, p <0.01), number of lesions treated (per additional lesion, OR 1.54, p <0.01), maximum balloon size (per millimeter increase, OR 1.57, p <0.05), American College of Cardiology/American Heart Association type C lesion (OR 1.68, p <0.05), sustained chest pain during procedure (OR 1.94, p <0.05), dissection (OR 2.05, p <0.05), and transient side branch occlusion (OR 4.54, p <0.05). Independent predictors for major CK-MB increase were chest pain at end of procedure (OR 9.66, p <0.001), type C lesion (OR 2.42, p <0.05), Canadian Cardiovascular Society angina class III to IV (OR 3.32, p <0.05), thrombus (OR 5.09, p = 0.001), and abrupt closure (OR 5.30, p <0.05). In conclusion, baseline clinical and angiographic characteristics and procedural complications were associated with minor and major CK-MB increases. Patients with chest pain at the end of the procedure were at the highest risk for major CK-MB increase.