Background: The evaluation of site-specific phenotype according to the topographic location of atherosclerotic lesions within the coronary tree has not been studied so far. The present study is based on the premise that the location of coronary plaques can influence their composition and degree of vulnerability. Aim: To evaluate different phenotypes of vulnerable coronary plaques across the three major coronary arteries in terms of composition, morphology, and degree of vulnerability, in patients with chest pain and low-to-intermediate probability of coronary artery disease, using coronary computed tomography angiography (CCTA) and a complex plaque analysis. Material and methods: This was a cross-sectional study on 75 subjects undergoing CCTA for chest pain, who presented at least one vulnerable coronary plaque (VP), defined as the presence of ≥1 CT vulnerability marker (low attenuation plaque, napkin-ring sign, spotty calcifications, positive remodeling). The study included per plaque analysis of 90 vulnerable coronary lesions identified in various locations within the coronary tree as follows: n = 30 VPs in the left anterior descending artery (LAD), n = 30 VPs in the circumflex artery (CXA), and n = 30 VPs in the right coronary artery (RCA). Results: The RCA exhibited significantly longer VPs (p = 0.001), with the largest volume (p = 0.0007) compared to those arising from the LAD and CXA. Vulnerable plaques located in the LAD exhibited a significantly more calcified phenotype (calcified volume: LAD – 44.07 ± 63.90 mm3 vs. CXA – 12.40 ± 19.65 mm3 vs. RCA – 33.69 ± 34.38 mm3, p = 0.002). Plaques from the RCA presented a more non-calcified phenotype, with the largest non-calcified (p = 0.002), lipid rich (p = 0.0005), and fibrotic volumes (p = 0.003). Low-attenuation plaques were most frequent in the RCA (p = 0.0009), while the highest vulnerability degree was present in lesions located in the LAD, which presented the highest number of vulnerability markers per plaque (p = 0.01). Conclusions: Vulnerable plaques arising from the right coronary artery are longer, more voluminous and with larger lipid and non-calcified content, whereas those located in the left anterior descending artery present a higher volume of calcium, but also a higher degree of vulnerability. The least vulnerable lesions were present in the circumflex artery.