The aim of this study was to demonstrate that the transluminal contrast attenuation gradient (TAG), a new CT imaging-derived marker of functional significance of a coronary stenosis, is directly associated with the vulnerability degree of atheromatous coronary plaques. Material and methods: This is a prospective study on 21 patients with 30 atheromatous plaques in the coronary arteries, who underwent cardiac computed tomography angiography (CCTA) for assessment of coronary plaques. Results: Twelve plaques were classified as vulnerable (40%) and 18 plaques (60%) as non-vulnerable. Plaques associated with a TAG value above 10 HU exhibited in a significantly higher proportion CCTA markers of plaque vulnerability, as compared to plaques in which the attenuation gradient was below 10 HU. TAG values >10 HU were associated with a higher amount of plaque volume (107.4 ± 91.2 mm3 vs. 56.0 ± 37.5 mm3, p = 0.009), necrotic core (32.5 ± 36.9 mm3 vs. 3.1 ± 3.2 mm3, p = 0.0003), and fibro-fatty tissue (17.7 ± 16.3 mm3 vs. 4.0 ± 2.6 mm3, p = 0.0002), as compared to those lesions with TAG values below 10 HU. Linear regression analysis revealed a significant correlation between TAG values and CCTA features of plaque instability: necrotic core (r = −0.73, p <0.0001), fibrofatty tissue (r = −0.63, p = 0.0002), and plaque volume (r = −0.48, p = 0.006). Conclusions: In patients with coronary artery disease, contrast attenuation gradient along the coronary plaques, determined by CCTA, correlates with CT markers of plaque vulnerability. Vulnerable coronary plaques are associated with a higher functional significance than the stable ones with a similar anatomic profile.