Granular medical-grade calcium sulfate hemihydrate (MGCSH) and negatively charged dextran beads (DB) were evaluated both separately and in combination in cranial defects. Thirty-six rats received bilateral parietal inlay reconstructions using MGCSH, MGCSH plus DB, or DB alone or the defects were left unfilled. Postoperative evaluation at 45, 90, and 135 days was done by visual inspection, caliper measurements of defect thickness, and histologic examination. The best fibro-osseous repair of the defects occurred with the use of MGCSH in combination with DB. Repair tissue, which was confluent with the adjacent cranium, was noted to have good thickness, and a high bone content. By contrast, defects repaired with either DB or MGCSH alone had poorer quality repair tissue, with concavities, voids, bead migration, decreased thickness, and minimal bony replacement/ingrowth. Unfilled control defects showed only a thin, friable, translucent connective tissue layer of repair. No method produced complete bony closure.