Background: Alveolar ridge preservation following tooth extraction remains a clinical challenge, necessitating guided bone regeneration (GBR). The aim of this study was to compare the biocompatibility and tissue response of an experimental resorbable collagen (rCOL) membrane reinforced by poly-lactic-co-glycolic acid to a commercially available non-resorbable titanium (Ti)-reinforced polytetrafluorethylene (rPTFE) membrane in a large translational (beagle) mandibular model. Materials and Methods: Beagles (N = 7) underwent bilateral extraction of mandibular premolars, with full-thickness flaps raised to expose the mandibular bone. Bilateral fourwalled semi-saddle defects (2 defects per animal) were created using a low-speed cylindrical burr under copious irrigation. Defects were filled with porcine xenograft (Xe) putty and covered with either an experimental rCOL, or commercially-available rPTFE (Cytoplast® Ti-150, Osteogenics Biomedical, Inc., Lubbock, TX, USA) membrane. Animals were allowed to heal for 6 weeks and defects were evaluated by microcomputed tomography (μCT) and histological analysis. Results: μCT demonstrated gradual bone ingrowth and bone graft bridging within the defects in both membrane groups. However, bone formation within the defects was significantly greater in defects treated with rCOL (27.15 ± 6.22 %) relative to rPTFE (17.84 ± 6.22 %) (p = 0.041). Histological evaluation demonstrated that the rPTFE group presented with inflammatory infiltrate and granulation tissue between the defect and membrane surface. In contrast, the defects covered by the rCOL membrane evidenced direct contact with newly formed osseous and connective tissue layers. Conclusions: rCOL membranes demonstrated superior healing outcomes characterized by minimal inflammation and higher levels of bone ingrowth within the defect site, compared to rPTFE counterparts.