The purpose of this study was to determine whether thin-capped fibroatheromata (TCFA) identified by virtual histology intravascular ultrasound (VH-IVUS) are associated with major adverse cardiac events (MACE) on individual plaque or whole patient analysis. Post-mortem studies have identified TCFA as the substrate for most myocardial infarctions. However, little is known about the natural history of individual TCFA and their link with MACE. VH-IVUS provides a method of identifying plaques in vivo that are similar (although not identical) to histologically defined TCFA, and has been validated in human atherectomy and post-mortem studies. One hundred seventy patients with stable angina or troponin-positive acute coronary syndrome referred for percutaneous coronary intervention (PCI) were prospectively enrolled and underwent 3-vessel VH-IVUS pre-PCI and also post-PCI in the culprit vessel. MACE consisted of death, myocardial infarction, or unplanned revascularization. In all, 30,372 mm of VH-IVUS were analyzed. Eighteen MACE occurred in 16 patients over a median follow-up of 625 days (interquartile range: 463 to 990 days); 1,096 plaques were classified, and 19 lesions resulted in MACE (13 nonculprit lesions and 6 culprit lesions). Nonculprit lesion factors associated with nonrestenotic MACE included VHTCFA (hazard ratio HR: 7.53, p = 0.038) and plaque burden >70% (HR: 8.13, p = 0.011). VHTCFA (HR: 8.16, p = 0.007), plaque burden >70% (HR: 7.48, p < 0.001), and minimum luminal area <4 mm(2) (HR: 2.91, p = 0.036) were associated with total MACE. On patient-based analysis, the only factor associated with nonrestenotic MACE was 3-vessel noncalcified VHTCFA (HR: 1.79, p = 0.004). VH-IVUS TCFA was associated with nonrestenotic and total MACE on individual plaque analysis, and noncalcified VHTCFA was associated with nonrestenotic and total MACE on whole-patient analysis, demonstrating that VH-IVUS can identify plaques at increased risk of subsequent events. The preservation of the association between VHTCFA and MACE despite various analyses emphasizes its biological importance.