Introduction: The presence of multiple high-risk prognostic features enhances risk-stratification of plaques prone to destabilization and major adverse cardiac events (MACE). Spatial superimposition of high-risk features (concordance) likely amplifies local risk. Local endothelial shear stress (ESS) and plaque structural stress (PSS) metrics predict MACE, but their spatial concordance and their location relative to the minimal lumen area (MLA) is unknown. If the highest-risk plaque area is distant from the MLA, then PCI of the MLA alone will leave high-risk plaque areas untreated. Purpose: To identify the site of high-risk features of low ESS and high PSS heterogeneity (HI) along the course of a plaque in patients who develop MACE, and the site of their spatial concordance relative to the MLA. Methods: We examined ESS, PSS, and PSS HI in 22 non-culprit lesions (NCL) leading to MACE, and 64 randomly selected control NCLs without MACE from the PROSPECT study. ESS was calculated by computational fluid dynamics and PSS by finite element analysis on co-registered lesions. We examined high-risk plaques with empirically-derived (ROC curve) ESS < 1.3 Pa and PSS HI > 0.29 in 16 lesions leading to future MACE, and 11 control lesions without MACE. Results: MACE outcomes were significantly more frequent in plaques with combined low ESS+high PSS HI vs plaques with low ESS alone (72.7% vs 27.3%, p<0.001) at 3 years follow-up. Of the 16 MACE plaques with both low ESS+high PSS HI, 14 exhibited high-risk values that were spatially concordant vs 2 that were discordant (87.5% v 12.5%, p=0.01). In the 14 plaques with concordant values, there were 26 focal plaque areas with high-risk concordance. The mean distance from the concordant high-risk areas to the MLA was 13.2 ± 11.6 mm (Figure). Conclusion: High-risk ESS and PSS measures frequently co-localize in plaques responsible for future MACE, and are substantially distant from the MLA. PCI of the MLA area alone may leave many high-risk areas untreated.