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Abstract Stent-grafts composed of expanded polytetrafluoroethylene (e-PTFE), polyethylene terephthalate (PET) and polyurethane (PU) are characterized by poor endothelialization, high modulus, and low compliance, leading to thrombosis and intimal hyperplasia. A composite synthetic/natural matrix is considered a promising alternative to conventional synthetic stent-grafts. This study aimed to investigate the efficacy of thermoplastic polyurethane (TPU) and gelatin (GL) blended nanofibers (NFs) covered stent-graft in the porcine iliac artery. Twelve pigs were randomly sacrificed 7 days (n = 6) and 28 days (n = 6) after stent-graft placement. The thrombogenicity score at 28 days was significantly increased compared at 7 days (p < 0.001). The thickness of neointimal hyperplasia, degree of inflammatory cell infiltration, and degree of collagen deposition were significantly higher at 28 days than at 7 days (all p < 0.001). The TPU and GL blended NFs-covered stent-grafts successfully maintained the patency for 28 days in the porcine iliac artery. Although thrombosis with neointimal tissue were observed, no subsequent occlusion of the stent-graft was noted until the end of the study. Composite synthetic/natural matrix-covered stent-grafts may be promising for prolonging stent-graft patency.