Large cranial defects do not always heal spontaneously, especially in humans; often they have to be obturated with metallic or acrylic fillers. Bilateral cranial trephine defects, measuring 14-20 mm in diameter, were created in three Rhesus monkeys, providing a typical primate model system for investigations in comparative physiology of bone regeneration. Each skull had one control and one experimental trephine defect. Control defects were implanted with bovine serum albumin (BSA). Experimental defects were implanted with 100-200 mg of a partially purified fraction of bovine bone morphogenetic protein (bBMP) in two monkeys. In one monkey, the BMP was incorporated in a 1:1 poly(lactic) poly(glycollic) acid copolymer, high-viscosity formula. The animals were killed at eight weeks, ten weeks, and 16 weeks after implantation. The tissue responses were analyzed by computed histomorphometry and routine histologic examination. At each time interval, the BMP implanted defects produced more complete regeneration than the control implants. The morphogenetic response occurred in the following sequences: mesenchymal cell proliferation, chondrogenesis, and increased bone formation. BMP-induced osteogenesis may initiate the regenerative process. The copolymer releases BMP but may constitute a barrier to the end stages of replacement by new bone, and would be more useful in a low-viscosity rapidly biodegradable form.