Background: The incidence of postprocedural creatine kinase (CK)-MB elevation to >3x the upper limit of normal after percutaneous coronary intervention (PCI) has been reported at rates of up to 18% in the bare metal stent era and is correlated with higher adverse cardiovascular outcomes. This study examined the incidence and prognostic significance of CK-MB elevations after drug-eluting stent (DES) implantation. Methods: The records of 2,537 patients who underwent DES implantation and completed ≥6 months' follow-up were evaluated. Patients with acute myocardial infarction and those who presented in cardiogenic shock and had elevated cardiac enzymes at baseline were excluded from the analysis. Of these, 179 patients (7.1%) had ≥3x postprocedural CK-MB and 2,358 patients had <3x CK-MB elevation. The composite end point of target vessel revascularization-major adverse cardiac events (TVR-MACE) at 6 months was compared between groups. Univariate and multivariate regression analyses were performed to identify predictors of adverse cardiac outcomes. Results: The patients with CK-MB ≥3x elevation had a higher number of diseased vessels (2.15 ± 0.86 vs. 1.81 ± 0.87; P < 0.001), higher prevalence of type C lesions (29.9% vs. 17.7%; P < 0.001), received a higher average number of stents, and total stented length (1.72 ± 0.89 vs. 1.49 ± 0.83; P < 0.001 and 37.4 ± 23.0 mm vs. 30.8 ± 20.7 mm; P = 0.0003, respectively), and had lower rates of clinical success (91.9% vs. 99.2%; P < 0.001). The 6-month and 1-year TVR-MACE rates were higher for the elevated CK-MB group (11.9% vs. 7.0%; P = 0.02 and 16.1% vs. 26.6%, respectively; P = 0.005). The rates of subacute thrombosis were also significantly higher in the group with elevated CK-MB (0.4% vs. 3.2%, P < 0.001). Though significant CK-MB release was a predictor of TVR-MACE after univariate analysis, multivessel PCI, subacute stent thrombosis, total stented length, and history of prior PCI were the only predictors after multivariate regression analysis. Conclusions: Postprocedural CK-MB ≥3x elevation following PCI with DES continues to be a marker for the complexity of coronary disease and lack of clinical success; and correlates with higher rates of subacute thrombosis as well as late adverse events at 6-months and 1-year postprocedure.