BACKGROUND: Mechanism of femoropopliteal in-stent restenosis has been underappreciated. AIM: The aim of this animal study was to elucidate vascular response after femoropopliteal bare nitinol self-expanding stents (SESs) implantation. METHODS: Misago, Smart Flex, or Innova stent was randomly implanted in 36 swine femoropopliteal arteries. At week 4, quantitative vessel analysis (QVA) was performed on 36 legs, of which 18 underwent histological evaluation after angiography. The remaining 18 legs underwent QVA and histological evaluation at week 13. RESULTS: Fibrin deposition was excessive at week 4. Internal elastic lamina (IEL) progressively enlarged over time, and vessel injury developed from mild level at week 4 to moderate level at week 13. Vessel inflammatory reaction was mild to moderate at week 4, and was moderate to severe at week 13. Increased fibrin deposition was an early-acting, IEL enlargement and increased vessel inflammation were long-acting, and increased vessel injury and giant cells infiltration were late-acting contributors to neointimal hyperplasia (NIH). Stent type altered time-dependent process of vessel injury, vessel inflammation, eosinophils and giant cells infiltration. Misago had less fibrin deposition and vessel enlargement, and less progressive vessel injury, vessel inflammation, and eosinophils and giant cells infiltration. Net lumen as assessed by percent diameter stenosis or minimum lumen diameter was preserved with Misago, but was not preserved with the other stents. CONCLUSIONS: In the context of bare nitinol SES platform with less progressive mechanical stress and inflammatory reaction, the advantage of less NIH outweighed the disadvantage of less vessel enlargement, leading to net lumen preservation.