A considerable number of patients with an acute coronary syndrome (ACS) who present with a 0 or low calcium score (CS) still demonstrate coronary artery disease (CAD) and significant stenosis. The aim of the present study was to evaluate the relation between the CS and the degree and character of atherosclerosis in patients with suspected ACS versus patients with stable CAD obtained by computed tomography angiography and virtual histology intravascular ultrasound (VH IVUS). Overall 112 patients were studied, 53 with ACS and 59 with stable CAD. Calcium scoring and computed tomography angiography were performed and followed by VH IVUS. On computed tomography angiography each segment was evaluated for plaque and classified as noncalcified, mixed, or calcified. Vulnerable plaque characteristics on VH IVUS were defined by percent necrotic core and presence of thin-cap fibroatheroma. If the CS was 0, patients with ACS had a higher mean number of plaques (5.0 ± 2.0 vs 2.0 ± 1.9, p <0.05) and noncalcified plaques (4.6 ± 3.5 vs 1.3 ± 1.9, p <0.05) on computed tomography angiography than those with stable CAD. If the CS was 0, VH IVUS demonstrated that patients with ACS had a larger amount of necrotic core area (0.58 ± 0.73 vs 0.22 ± 0.43 mm², p <0.05) and a higher mean number of thin-cap fibroatheromas (0.6 ± 0.7 vs 0.1 ± 0.3, p <0.05) than patients with stable CAD. In conclusion, even in the presence of a 0 CS, patients with ACS have increased plaque burden and increased vulnerability compared to patients with stable CAD. Therefore, absence of coronary calcification does not exclude the presence of clinically relevant and potentially vulnerable atherosclerotic plaque burden in patients with ACS.