The aim of this study was to evaluate the healing response to a new commercially available ePTFE-covered stent graft used to create transjugular intrahepatic portosystemic shunts (TIPS) in an animal model with and without intraluminal irradiation. The study was designed for ten domestic normotensive pigs. The TIPS was created using a ePTFE-covered stent graft (Viatorr, Gore, Flagstaff, Ariz.). Five animals were scheduled for intraluminal irradiation with iridium 192 immediately after TIPS creation with a dosage of 18 Gy. Shunt venograms were performed every 2 weeks. Animals from the irradiated and non-irradiated group were killed at 2-week intervals. Maximum follow-up was planned for 8 weeks in each group, with two animals in reserve. Gross specimen evaluation and histological examination, including scanning electron microscopy, was performed. Two animals died from interventional complications. In the irradiation group, one shunt occlusion and one stenosis occurred after 2 weeks. The stenosis regressed until the end of the 8-week follow-up period and probably was caused by a resolving thrombus. In the non-irradiated group, no shunt dysfunction was observed. One animal died early due to encephalopathy. Histology revealed an increased inflammatory reaction in the irradiation group, a lesser degree of incorporation of the stent graft, and a lesser degree of endothelialization of the inner surface compared with the non-irradiated group. No significant foreign body reaction was found at any time in any of the animals. The Viatorr stent graft was well tolerated in the pig model. Intraluminal irradiation seemed to have an adverse effect on the healing response. The TIPS patency was prolonged in both the irradiated and non-irradiated group compared with data from the literature; however, seemingly better results were observed in the non-irradiated group.