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Simple Summary: Giant cell tumor of bone (GCTB) is an intermediate bone neoplasm which consists of several cell populations, including the neoplastic "stromal" cells. These cells harbor a mutation in one of the histone H3.3 genes (H3F3A), and are therefore considered as the driving component of GCTB. This mutation causes changes in the epigenetic landscape, leading to aberrant gene expression patterns that may drive tumor growth. Surgery is currently the only curative treatment option because contemporary systemic therapies cannot remove the neoplastic cells from GCTB lesions, leading to re-outgrowth of the tumor when the treatment is discontinued. Therefore, the aim of this study was to explore whether therapeutic targeting of the epigenome can eliminate the neoplastic cells from GCTB lesions. The findings from this study indicate that histone deacetylase (HDAC) inhibitors may represent such a treatment strategy, which could improve the quality of life of GCTB patients who currently require life-long treatment. The neoplastic "stromal" cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic "stromal" cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen (n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells. Transcriptome analysis revealed that the neoplastic cells expressed all HDAC isoforms, except for HDAC4. Therefore, five HDAC inhibitors targeting different HDAC subtypes were selected for further studies. All GCTB cell lines were very sensitive to HDAC inhibition in both 2D and 3D in vitro models, and inductions in histone acetylation, as well as apoptosis, were observed. Thus, HDAC inhibition may represent a promising therapeutic strategy to eliminate the neoplastic cells from GCTB lesions, which remains the paramount objective for GCTB patients who require life-long treatment with denosumab.