Several procedures have been used to regenerate localized bone defects around dental implants or to increase bone volume at an implant site, including bone grafting, placement of barrier membranes, and use of bone graft substitutes. This study sought to determine whether the bone graft substitute natural coral skeleton (NCS), with or without a protective polymer mesh, enhances bone formation in rat critical size craniotomy defects. The control group (1) had unfilled defects, while the defects in the four experimental groups (six rats each) were treated with: (2) an NCS disc of the size of the defect; (3) NCS granules; (4) NCS granules covered by a polyglactin 910 mesh; and (5) polyglactin 910 mesh alone. Undecalcified histologic sections were assessed by histomorphometric measurements 28 days later. The three NCS groups showed improved bone formation, which was statistically significant in groups (2) (NCS disc) and (4) (NCS granules covered by polyglactin 910 mesh). Group 4 had more bone formation than all the other groups. Polyglactin 910 mesh alone (group 5) produced no greater bone formation than the unfilled control. It is concluded that the bone formation obtained with NCS granules is enhanced when the particles are retained at the site of the defect with a protective mesh. Keywords: bone graft substitute, bone regeneration, natural coral, critical size defects, polymer mesh