Nell-1 (Nel-like molecule-1; Nel: protein strongly expressed in neural tissue containing epidermal growth factor-like domain) is a promising osteoblast-specific growth factor for osteoinductive therapies that may circumvent adverse effects, such as nonspecific function and ectopic bone formation, associated with more established osteogenic growth factors such as bone morphogenetic proteins. Beta-tricalcium phosphate (beta-TCP), an osteoconductive, biodegradable ceramic biomaterial, has been used successfully to deliver osteoinducers for bone regeneration. The aim of this study was to develop a carrier system for efficiently delivering biologically active Nell-1 protein. After a 40% initial burst release, beta-TCP particles retained the majority of adsorbed Nell-1 protein in vitro. To test this system in vivo, L4/L5 spinal fusion was performed in three groups of rats (n = 8 each): (1) 5 microg Nell-1 in beta-TCP/demineralized bone matrix putty (DBX); (2) 2.5 microg Nell-1 in beta-TCP/DBX; (3) beta-TCP/DBX only. Fusion was assessed by radiography, palpation, microcomputed tomography, and histological analysis. After 4 weeks, 75% of Nell-1-treated animals exhibited fusion, with a significant increase in new bone volume, whereas only 25% of Nell-free control animals exhibited fusion. Our findings suggest that beta-TCP/DBX can increase both the biochemical stability and biological efficiency of Nell-1 protein.