The adverse long-term events in first-generation drug-eluting stents were associated with chronic inflammatory response to the polymer. As an alternative, stents with biodegradable polymers emerged, whose effects on the vascular response are not yet fully known. Our objectives were to study the adventitial response to the stent implantation and the role of the polymeric vehicle. A histological (Haematoxylin-Eosin, Verhoeff van Gieson) and immunohistochemical (von Willebrand factor, alpha-smooth muscle actin) analysis were performed on resin-embedded arterial sections from fifteen Large White pigs, 28 days after the random implantation in the coronary arteries of: a chromium-cobalt stent and a stent coated with a permanent polyacrylate or biodegradable poly(D,L)-lactic-co-glycolic polymer, the two latter ones are loaded with sirolimus. Independent of the stent, the adventitial inflammation was associated with the adventitial area (P = 0.006 8) and the inflammation score (P = 0.037 1); and the adventitial actin-positive cells with the vascular damage (P = 0.001 2). A significant relationship was observed between the greater percentages of the restenosis and the more intense inflammation (P = 0.035 1) and the actin-positive cells (P = 0.011 9) in the adventitia. The polymeric vehicle increased the adventitial actin-positive cells (P = 0.018), independent of the type of polymer. The adventitial changes seem to be related to the restenosic process 28 days after the coronary stenting. Further investigations are necessary to confirm the role of the polymeric vehicle on the adventitial histopathological changes.