Porcine small intestinal submucosa extracellular matrix (CorMatrix; CorMatrix Cardiovascular, Rosewell, GA) is a relatively novel tissue substitute used in cardiovascular applications. We investigated the biological reaction and remodelling of CorMatrix as a tri-leaflet valved conduit in a pig model. We hypothesized that CorMatrix maintains a durable architecture as a valved conduit and remodels to resemble surrounding tissues. We fashioned the valved conduit using a 7 × 10 cm 4-ply CorMatrix sheet and placed it in the thoracic aorta of seven landrace pigs for 3, 4, 5 and 6 months. Biodegradation, replacement by native tissue, strength and durability were examined by histology, immunohistochemistry and mechanical testing. Four pigs, one per time frame, completed the study. The conduit lost its original architecture as a tri-leaflet valve due to cusp immobility, subsequent attachment to the wall segment and consequent maintenance of a thick arterial wall-like structure. Scaffold resorption was incomplete, with disorganized inconsistent spatial and temporal degradation even at 6 months. Fibrosis, scarring and calcification started at 4 months and chronic inflammation persisted. The partially remodelled scaffold did not resemble the aortic wall, suggesting impaired remodelling. Mechanical testing showed progressive weakening of the tissues over time, which were liable to breakage. CorMatrix is biodegradable; however, it failed to remodel in a structured and anatomical fashion in an arterial environment. Progressive mechanical and remodelling failure in this scenario might be explained by the complexity of the conduit design and the host's chronic inflammatory response, leading to early fibrosis and calcification.