According to pathologic studies, the content of a necrotic core increases in a “linear fashion” as plaque enlarges. In addition, these 2 plaque characteristics have been associated with plaque vulnerability. This study assessed the relation between plaque cross-sectional area (CSA) and content of necrotic core (NC). Twenty-five patients (75 arteries) with acute coronary syndrome were studied. In total, 7,834 CSAs were analyzed. An analysis of plaque CSA in percentiles was performed (median 5.5 mm², interquartile range 3.7 to 7.8); subsequently, plaque CSA values were categorized as small (≤3.7 mm²), medium (>3.7 to ≤7.8 mm²), and large (>7.8 mm²). There was a difference in content of the NC between arteries within each plaque CSA category. This observation was confirmed in a multivariate analysis in which only 2 variables remained statistically significant, plaque CSA (estimate 1.34, SE 0.05, p <0.0001) and studied artery (left anterior descending coronary artery, estimate 0.29, SE 0.08, p = 0.0003; left circumflex coronary artery, estimate 0.23, SE 0.07, p = 0.0014; and these vs the right coronary artery). In conclusion, the NC and plaque increase in patients with acute coronary syndromes.