The aim of this preliminary study was to assess the effectiveness of transluminal contrast attenuation gradient (TAG) determined by computed tomographic angiography (CTA), for the evaluation of the functional significance of coronary artery stenoses in patients with acute coronary syndromes produced by vulnerable coronary plaques, and to demonstrate the correlation between this new parameter and the vulnerability markers of the culprit lesions. Material and methods: This is a preliminary pilot study on 10 patients with acute coronary syndromes– unstable angina type, who underwent CTA for the assessment of coronary lesions, followed by invasive angiography and the determination of fractional flow reserve (FFR) prior to a revascularization procedure. Patients were divided into 2 groups, according to their FFR values: Group 1 consisted of 6 patients with an FFR value <0.8 (functionally significant lesion), and Group 2 consisted of 4 patients who presented an FFR value >0.8 (functionally non-significant lesion). Results: FFR values were 0.64 ± 0.07, 95% CI: 0.5–0.7 in Group 1, and 0.86 ± 0.05, 95% CI: 0.7–0.9 in Group 2. Plaques associated with an FFR<0.8 presented a higher amount of plaque volume (192.7 ± 199.7 mm3 vs. 42.1 ± 27.3 mm3, p = 0.1), necrotic core (66.7 ± 72.9 mm3 vs. 10.0 ± 9.3 mm3, p = 0.1), and fibro-fatty tissue (29.7 ± 37.4 mm3 vs. 6.2 ± 3.8 mm3, p = 0.2). At the same time, TAG significantly correlated with the presence of a functionally significant lesion. Coronary lesions associated with low FFR presented significantly higher values of TAG along the plaque as compared with lesions with FFR values >0.8 (TAG values 22.1 ± 5.8 HU vs. 11.7 ± 2.5 HU, p = 0.01). Linear regression identified a significant correlation between TAG and FFR values as a measure of functional significance of the lesion (r = 0.7, p = 0.01). Conclusions: Contrast attenuation gradient along the culprit lesion, determined by CTA, correlates with the FFR values and with CT markers of plaque vulnerability, indicating that the presence of vulnerability features inside a coronary plaque could increase the functional significance of a coronary lesion.