Giant cell tumor (GCT) of bone is a benign type of tumor, but the presence of hyperactive multinucleated giant osteoclasts cause local osteolytic lesions, increasing morbidity in patients. To specifically target hyperactive multinucleated giant osteoclasts in GCTs, one would envisage the usage of osteoclast inhibitors or genetic modulation of osteoclastogenesis. Recently, we have found that the translationally regulated balance between the transcription factor C/EBPβ long (LAP) and short (LIP) protein isoforms regulates osteoclast differentiation. Here, we report that GCTs express high levels of the LIP C/EBPβ isoform, which in mice cause giant osteoclast formation. In mice, inhibition of mTOR activity by rapamycin decreased osteoclast differentiation by shifting the alternative translation initiation of C/EBPβ isoforms towards LAP. Similarly, rapamycin treatment of GCT cell cultures derived from seven different patients strongly reduced formation of giant osteoclasts and bone resorption. This was accompanied by an increase in MafB, previously shown to be the mediator of the effect of rapamycin on osteoclast differentiation in mice. These data suggest that C/EBPβ is a determinant of giant osteoclast formation in GCT and that pharmacological adjustment of the C/EBPβ isoform ratio could serve as a potential novel therapeutic approach.