Background - Elevation of serum creatine kinase MB fraction (CK-MB) after percutaneous coronary interventions has been associated with early and late mortality; however, the pathogenesis of CK-MB elevation is still unknown. We hypothesized that CK-MB elevation was related to atherosclerotic plaque burden as assessed by preintervention intravascular ultrasound (IVUS). Methods and Results - We studied 2256 consecutive patients who underwent intervention of 2780 native coronary lesions and had complete high-quality preintervention IVUS imaging in the era before routine use of platelet glycoprotein IIb/IIIa inhibitors. Patients were divided into 3 groups: CK-MB within normal range (1675 patients; 2061 lesions); CK-MB elevation 1 to 5 times upper limit of normal (292 patients; 355 lesions); and CK-MB elevation ≥5 times upper limit of normal (289 patients; 364 lesions). Qualitative angiographic lesion morphology and quantitative analysis were similar among the 3 groups. On preintervention IVUS, progressively more reference segment and lesion site plaque burden and lesion site calcium occurred in the groups with CK-MB elevation. Positive remodeling was more common in lesions with CK- MB elevation. As levels of CK-MB increased, cross-sectional narrowing (percentage plaque burden) increased, both at the reference site (mean cross- sectional narrowing values were 45.1%, <49.3%, and <52.2% for normal CK-MB, 1 to 5 times upper limit of normal, and ≥5 times upper limit of normal groups, respectively; P=0.03) and at the lesion site (81.9%, <85.4%, and < 87.1%, respectively; P=0.04). Multivariate analysis indicated that de novo lesions, atheroablative technique, plaque burden at the lesion and reference segments, and final minimal lumen diameter were independent predictors of CK-MB elevation. Conclusions - CK-MB elevation correlates with a greater atherosclerotic plaque burden. CK-MB elevation after intervention may be a marker of diffuse atherosclerotic disease or a consequence of catheter-based intervention in more diseased arteries or both.