Background: In view of the potential drug synergy, implanting another different drug-eluting stent (DES) seems to be a good option for reducing DES failure. However, whether the implantation sequence of hybrid overlapping DES will distinctly influence on the intimal growth or endothelial function remains unclear. Methods: A total 21 rabbits were randomized to receive overlapping stents implantation in their right iliac arteries for 3 months [distal Cypher + proximal Taxus (C+T, n=7), distal Taxus + proximal Cypher (T+C, n=7) and bare metal stent (BMS) + BMS (B+B, n=7)]. Endothelial function was evaluated during follow-up arteriography with acetylcholine (ACh) provocation test. Furthermore, a total 36 consecutive patients (pts) receiving hybrid overlapping Cypher and Taxus stents for diffuse long lesion were enrolled from June 2004 to December 2007. Angiographic and clinical outcomes were evaluated at 6 months. Results: The preclinical angiographic data showed higher late loss when the Cypher was implanted in the distal area. The incidence of ACh induced significant spasm was significantly higher in rabbits when the Cypher stent was implanted in the distal area, too. Notably, rabbits with distal Cypher implantation showed 3 cases of stent fracture whereas the other groups had no stent fracture cases. However, clinical studies showed that different hybrid DES overlapping implantation had similar mid-term angiographic and clinical outcomes (Table 1 & 2). Conclusions: In the preclinical evaluation of hybrid overlapping stenting, distal Cypher and proximal Taxus implantation in a rabbit iliac artery showed higher incidence of late loss, endothelial dysfunction and more frequent Cypher stent fractures but these untoward events were not observed in the clinical studies.