Cigarette smoking is a major risk factor in the progression of atherosclerosis and has been shown to cause endothelial dysfunction, inflammation, and modification of lipid profile. However, its role in the pathogenesis of vulnerable coronary plaque remains unknown. We investigated the relationship between cigarette smoking and the development of vulnerable coronary artery plaque using virtual histology intravascular ultrasound (VH-IVUS). Data from consecutive patients who underwent VH-IVUS assessment of native coronary artery stenosis during clinically indicated cardiac catheterization at our institution over a 2-year period were analyzed. Baseline demographic and study characteristics were collected on all patients. Coronary plaque compositions of the culprit lesion were compared on bivariate and multivariate analysis. We analyzed data on 160 patients with a mean age of 60 ± 11 years. Sixty-nine percent of these patients were admitted for acute coronary syndrome, 31% were smokers, and the mean plaque burden was 66%. On average, 58% of these plaques were fibrous, 19% were fibro-fatty, 18.3% had a necrotic core, and 5.4% were composed of dense calcium. Cigarette smokers had a higher burden of necrotic core (20.7% vs 17.2%; P≤.04). On multivariate analysis, cigarette smoking was independently associated with a 4.54% increase in the burden of necrotic core (P≤.01). Older age (>80 years) was also a predictor of higher necrotic core burden (P≤.02). In conclusion, cigarette smoking is associated with a higher burden of necrotic core in coronary atherosclerotic plaques. This may represent one of the mechanisms for increased cardiovascular events.