Aims: Relative plaque composition, more than its morphology alone, is thought to play a pivotal role in determining propensity to vulnerability. Thus, we investigated in vivo whether the distance from coronary ostium to plaque location independently affects plaque composition in humans. This may help explaining the recently reported non-uniform distribution of culprit lesions along the vessel in acute coronary syndromes. Methods and results: In 51 consecutive patients(45 men), aged 38-76 years(mean age: 58± 10), a non-culprit vessel was investigated through spectral analysis of IVUS radiofrequency data(IVUS Virtual HistologyTM). The study vessel was the left anterior descending artery in 23(45% ) patients; the circumflex artery in nine(18% ), and right coronary artery in 19(37% ). The overall length of the region of interest, subsequently divided into 10 mm segments, was 41.5± 13 mm long(range: 30.2-78.4). No significant change was observed in terms of relative plaque composition along the vessel with respect to fibrous, fibrolipidic, and calcified tissue, whereas the percentage of lipid core resulted to be increased in the first(median: 8.75% ; IQR: 5.7-18) vs. the third(median: 6.1% ; IQR: 3.2-12)(P=0.036) and fourth(median: 4.5% ; IQR: 2.4-7.9)(P=0.006) segment. At multivariable regression analysis, distance from the ostium resulted to be an independent predictor of relative lipid content [β =-0.28(95% CI:-0.15,-0.41)], together with older age, unstable presentation, no use of statin, and presence of diabetes mellitus. Conclusion: Plaque distance from the coronary ostium, as an independent determinant of relative lipid content, is potentially associated to plaque vulnerability in humans. Thus, we investigated in vivo whether the distance from coronary morphology to plaque composition, more than its morphology from humans. This may help explaining the recently reported non-uniform distribution of culprit lesions along the vessel in acute coronary syndromes. Methods and results: In 51 consecutive patients (45 men), aged 38-76 years (mean age: 58 ± 10), a non-culprit The study vessel was the left anterior descending artery in 23 (45%) patients; the circumflex artery in nine (18%), and the right coronary artery in 19 ( 37%). The overall length of the region of interest, subsequently divided into 10 mm segments, was 41.5 ± 13 mm long (range: 30.2-78.4). No significant change was observed in terms of relative plaque composition alo ng the vessel with respect to fibrous, fibrolipidic, and calcified tissue, while the percentage of lipid core resulted to be increased in the first (median: 8.75%; IQR: 5.7-18) vs. the third (median: 6.1% At multivariable regression analysis, distance from the ostium resulted to be an independent predictor of relative lipid content (P = 0.036) and fourth (median: 4.5%; IQR: 2.4-7.9) [β = -0.28 (95% CI: -0.15, -0.41)], together with older age, unstable presentation, no use of statin, and presence of diabetes mellitus. Conclusion: Plaque distance from the coronary ostium, an independent determinant of relative lipid content, is potentially associated to plaque vulnerability in humans.