NELL-1 (NEL-like Protein 1) is an osteoinductive protein with increasing usage as a bone graft substitute in preclinical animal models. NELL-1 was first identified to have bone-forming properties by its overexpression in fusing cranial sutures. Since this time, addition of recombinant NELL-1 has been used to successfully induce bone formation in the calvarial, axial and appendicular skeleton. With increasing interest in the use of NELL-1 as a bone-graft substitute, we sought to examine the expression of NELL-1 in a wide spectrum of benign and malignant bone-forming skeletal tumors. Immunohistochemical expression was examined in human pathologic specimens. Quantitative RT-PCR evaluated NELL-1 expression among OS cell lines in vitro. Results showed NELL-1 expression in all bone tumors. Likewise, all OS cell lines demonstrated increased NELL-1 expression in comparison to non-lesional human bone marrow stromal cells. Among, benign bone tumors (osteoid osteoma and osteoblastoma), strong and diffuse staining was observed, which spatially correlated with markers of osteogenic differentiation. In contrast, a relative reduction in NELL-1 staining was observed in osteosarcoma, accompanied by increased variation between tumors. Among osteosarcoma specimens, NELL-1 expression did not correlate well with markers of osteogenic differentiation. Surprisingly, among osteosarcoma subtypes, fibroblastic osteosarcoma demonstrated the highest expression of NELL-1. In summary, NELL-1 demonstrates diffuse and reliable expression in benign but not malignant bone-forming skeletal tumors. Future studies will further define the basic biologic, diagnostic and prognostic importance of NELL-1 in bone neoplasms. (C) 2015 Elsevier Inc. All rights reserved.