Bone giant-cell granuloma (GCG) is a non-neoplastic lesion. Hypoxia induces drug resistance in clinical tumors. The concept between drug resistance and apoptosis has been well defined but the relationship between reduced oxygen species and apoptosis is not a one-way story. Therefore, this study is an attempt to investigate the anti-apoptotic role of Bcl₂ gene and Bcl₂ protein in the hypoxia induced chemo-resistance of aggressive GCG. Forty cases of buffered formalin-fixed, paraffin embedded tissues of previously diagnosed cases of aggressive CGG were selected. Serial sections of 3 μm thickness were utilized for the detection of Bcl₂ using t (14;18) (q32;q21) IGH/Bcl₂ interphase Fluorescent in situ hybridization (FISH) and to assess the immunohistochemical expression of CAIX, MDR-1 and Bcl₂. All studied cases were positive for CAIX and MDR-1 while they were negative for Bcl₂ protein. FISH revealed normal Bcl₂ gene with no cytogenetic aberrations among the studied cases. In the light of the findings of this study, we could conclude that hypoxia might play a role in the pathogenesis of aggressive GCG and could induce their chemo-resistance. Thus, tissue oxygenation could participate in the treatment of these lesions and might inhibit their expansion. Moreover, Bcl₂ pathways haven't been implicated in aggressive GCG as Bcl₂ gene is normal in all cases. Therefore, any treatment options based on the anti-apoptotic Bcl₂ pathways for aggressive GCG must be avoided as they are ineffective.