Promoting rapid adhesion of endothelial cells is of significance for the viability of vascular grafts for small-diameter blood vessels (SDBVs) made of expanded polytetrafluoroethylene (ePTFE). Many physical and chemical surface modification methods have been developed to overcome the inertness of ePTFE and to promote cell adhesion. In this study, a biomimetic poly(ε-caprolactone) (PCL) shish-kebab microstructure was formed on the fibrillated domains of ePTFE through induced crystallization. The surface morphology and chemistry, mechanical property, cytocompatibility, and endothelial cell adhesion of PCL shish-kebab modified ePTFE were investigated. The effectiveness of and synergy between this physical topology modification and the traditional chemical RGD dig-coating in terms of cell adhesion were also evaluated. The positive effect of the shish-kebab structure on cell adhesion was found to be more significant than that of RGD coating, and there is a strong synergy between ePTFE surface modification and RGD coating. The biomimetic shish-kebab structure could be a promising material platform for further grafting and/or surface functionalization of ePTFE for other tissue engineering applications.