Introduction: Low local endothelial shear stress (ESS) is associated with coronary plaque development and progression. Both low ESS and large lipid cores are associated with coronary events, yet it is unknown whether low ESS co-localizes with large lipid core plaques (LCP) to synergistically promote plaque progression and destabilization. Methods: In this descriptive pilot study, near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) was performed in 32 arteries in 28 patients (age 63 ± 11 yrs, 68% male) with CAD (93% ACS). Large LCP were defined by a NIRS maximum lipid core burden index (LCBImax) >400. Arteries were divided into those with and without large LCP. 2-plane coronary angiography and IVUS images were used to create 3-D reconstructions of each artery, which were divided into 3-mm segments. Local ESS was calculated with computational fluid dynamics. Results: Arteries with large LCP (n=17) exhibited lower minimal ESS (0.36±0.19 Pa vs. 0.73±0.43 Pa [p=0.005]), but similar highest ESS (7.34±3.83 vs. 8.11±6.96 Pa [p=0.69]) and minimum lumen area (3.84± 1.41 mm2 vs. 5.06 ± 2.56 mm2 [p=0.06]) vs. arteries without large LCP (n=15). In the 3mm segments adjacent to the LCBImax location, low ESS (<= 1.0 Pa) was 31% more frequent than high ESS (>= 3.5 Pa) (p=0.25), and 54% more frequent than high ESS among lesions without large LCP (p=0.07) (Figure 1; vasculoprotective physiologic ESS values [1.1-3.4 Pa] not shown). Conclusions: Pro-inflammatory low ESS is significantly lower in arteries with large LCP compared to arteries without large LCP and may contribute to plaque destabilization. High ESS is also present at large LCP, and may contribute to plaque destabilization, but through different mechanisms. Low ESS may contribute to plaque progression among plaques without large LCP. Prospective longitudinal studies are necessary to determine which local ESS environment synergistically acts with large LCP to promote plaque progression and destabilization. [ABSTRACT FROM AUTHOR]