Background-Lack of re-endothelialization and neointimal coverage on stent struts has been put forward as the main underlying mechanism leading to late stent thrombosis. Incomplete stent apposition (ISA) has been observed frequently in patients with very late stent thrombosis after drug eluting stent implantation, suggesting a role of ISA in the pathogenesis of this adverse event. The aim of this study was to evaluate the impact of different degrees of ISA severity on abnormal shear rate and healing response with coverage, because of its potential implications for stent optimization in clinical practice. Methods and Results-We characterized flow profile and shear distribution in different cases of ISA with increasing strut-wall detachment distance (ranging from 100 to 500 mu m). Protruding strut and strut malapposed with moderate detachment (ISA detachment distance <100 mu m) have minimal disturbance to blood flow as compared with floating strut that has more significant ISA distance. In vivo impact on strut coverage was assessed retrospectively using optical coherence tomography evaluation on 72 stents (48 patients) sequentially at baseline and after 6-month follow-up. Analysis of coverage revealed an important impact of baseline strut-wall ISA distance on the risk of incomplete strut coverage at follow-up. Malapposed segments with an ISA detachment <100 mu m at baseline showed complete strut coverage at follow-up, whereas segments with a maximal ISA detachment distance of 100 to 300 mu m and >300 m had 6.1% and 15.7% of their struts still uncovered at follow-up, respectively (P<0.001). Conclusions-Flow disturbances and risk of delayed strut coverage both increase with ISA detachment distance. Insights from this study are important for understanding malapposition as a quantitative, rather than binary phenomenon (present or absent) and to define the threshold of ISA detachment that might benefit from optimization during stent implantation.