The resistance of two biomaterials, one synthetic and one biologic in origin, to deliberate bacterial infection was compared in a dog model of orthopedic soft tissue reconstruction. Twenty‐four adult female dogs were randomly divided into two equal groups and a 2.0‐cm‐round full‐thickness defect was created on the lateral surface of the stifle joint, leaving only the synovium and skin intact. The defect was surgically repaired with either Dacron™ mesh or a porcine derived extracellular matrix (ECM) scaffold material. The repair site was inoculated with 1 × 10⁸ Staphylococcus aureus at the time of surgery and the dogs were survived for 28 days. Results showed a chronic pyogranulomatous inflammatory response at the Dacron™ implant sites versus a constructive tissue‐remodeling response without residual inflammation at the ECM implant site. Three dogs in the group receiving the Dacron™ mesh were treated with Keflex™ (500 mg bid × 7 days) for signs of septicemia. A quantitative bacterial count of the implant sites at the time of sacrifice showed 6.52 × 10⁵ ± 1.2 × 10⁶ and 6.5 × 10² ± 1.8 × 10³ bacteria per gram of tissue for the Dacron™ and ECM scaffold sites, respectively (P < .03). The ECM implant material was more resistant than the synthetic implant material to persistent infection following deliberate bacterial contamination and the ECM scaffold supported constructive tissue remodeling. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 67B: 648–654, 2003