The majority of neurotrophic tyrosine receptor kinase (NTRK) rearranged neoplasm occur either in the superficial or deep soft tissues of extremities or trunk. Occasionally, it arises in visceral organs. However, occurrence as a primary osseous tumor has not been documented thus far. Herein, we describe a unique case of a NTRK rearranged neoplasm that presented as a primary bony lesion. The tumor occurred in a 21-year-old woman who presented with an increasing pain of the right lower extremity. Radiologic examinations revealed a destructive lytic lesion located in the lower portion of the right femur. Histologically, the tumor was composed of haphazard fascicles of monomorphic spindle cells displaying mild nuclear atypia and rare mitotic activity. Immunohistochemically, the tumor cells only showed focal staining of panTRK and S100 protein. Fluorescence in situ hybridization analysis was tentatively performed with utilization of break-apart probes of NTRK1/NTRK2/NTRK3 genes. An unexpected NTRK3 rearrangement was identified. Subsequent next generation sequencing (RNA-seq) revealed HMBOX1exon6::NTRK3exon 14 fusion. Our study illustrates, albeit extremely rare, NTRK rearranged neoplasm can arise as a primary bony lesion. In addition, we describe a novel HMBOX1::NTRK3 fusion which has not been documented before. This article is protected by copyright. All rights reserved.