Introduction: Plaque natural history is related to local shear stress, and shear stress has been shown to be heterogeneously distributed along the length of individual plaques. We investigated the longitudinal spatial heterogeneity of plaque progression/regression/quiescence in human coronary arteries. Methods: 591 coronary arteries from 302 patients with coronary disease who presented with an acute coronary syndrome from the PREDICTION study were investigated for local plaque progression/regression/quiescence patterns in non-culprit plaques after 6-10 month FU. Arterial geometry was derived from angiography/IVUS-based vascular profiling and reported in 3 mm segments. Plaques were defined as >3 consecutive segments with maximal wall thickness>0.5 mm. Plaque progression was defined as >5% increase, regression as <-5% decrease, and quiescence as no change in plaque burden (plaque area/ total vessel area * 100%). Results: 5658 3mm-segments of 661 plaques were analyzed. Plaque burden changes ranged from -22% to +20%. Among all plaques, 56% showed segments with plaque progression, 60% with regression and 96% with quiescence. On average, 17% of the plaque length displayed plaque progression, 20% regression and 63% quiescence. The presence and number of natural history features (progression, regression, quiescence) within the individual plaques were significantly related to plaque length using logistic mixed model regression analysis (figure). Conclusions: Coronary plaque natural history is extremely heterogeneous along the length of an individual plaque. These observations may explain why revascularization of a focal severe obstruction in the ISCHEMIA trial did not affect clinical outcomes, since remaining high-risk plaque up- or down-stream from the revascularization may have led to future cardiac events.