Naturally derived extracellular matrix (ECM) scaffolds have been successfully used to promote constructive remodeling of injured or missing tissue in a variety of anatomical locations, including abdominal wall repair. Furthermore, ECM scaffolds have shown the ability to resist infection and adhesion formation. The present study investigated the utility of an ECM scaffold, specifically, porcine urinary bladder matrix (UBM), for repair of a 5 × 5 cm full-thickness lateral thoracic wall defect in a canine model ( n = 6) including 5-cm segments of the 6th and 7th rib. The resected portion of the 7th rib was replaced as an interpositional graft along with the UBM scaffold. As a control, a Gore-Tex patch was used to repair the same defect ( n = 2). The control animals healed by encapsulation of the Gore-Tex patch by dense collagenous tissue. The remodeled UBM grafts showed the presence of site-specific tissue, including organized fibrous connective tissue, muscle tissue, adipose tissue, and bone. Upon fluoroscopic examination, it was shown that both bony defects were replaced with new calcified bone. In the 6th rib space, new bone bridged the entire span. In the 7th rib space, there was evidence of bone formation between the interpositional graft and the existing bone, as well as de novo formation of organized bone in the shape of the missing rib segment parallel to the interpositional graft. This study shows that a naturally occurring ECM scaffold promotes site-specific constructive remodeling in a large thoracic wall defect.