Purpose: The objective of the present study was to histologically evaluate barrier durability and host tissue response of new prototype collagen membranes in comparison to clinically available collagen and synthetic polymer membranes. Materials and Methods: The experimental study was conducted in 20 rabbits with 4 different healing periods of 2, 6, 12, and 28 weeks. Following surgical exposure of the calvarium, 6 circular bone defects (diameter 4 mm, depth 1.5 mm) were drilled into the outer cortex. After the bone had been removed, each defect was covered with 1 of 6 different membranes: 3 collagen prototype membranes, a Bio-Gide collagen membrane (BG), a glycolide-lactide-trimethylene carbonate Osseoquest membrane (OQ), and a polylactide Atrisorb membrane (AS). Histological analysis was performed following staining with toluidine blue and transversal sectioning of the calvarial bone. Results: All collagen membranes showed similar tissue integration characterized by fibrous encapsulation with differentiation of a periosteumlike tissue upon the external bony surface. One prototype collagen membrane displayed clearly longer membrane integrity. The evaluated synthetic membranes demonstrated extended barrier durability but also exhibited inflammatory foreign-body reactions. Discussion: Recent experimental investigations have shown that degradation of collagen membranes may begin within days to weeks of membrane placement. This was confirmed in the present study. However, 1 of the chemically modified collagen prototype membranes exhibited prolonged membrane integrity in the absence of an inflammatory tissue response. Conclusion: Further investigation of the prototype membrane that showed prolonged membrane integrity to evaluate its potential in GBR procedures is needed. Keywords: aliphatic polymers, bioresorbable barrier membranes, collagen, membrane degradation, tissue reactions