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Background: A giant cell tumor (GCT) of bone is a benign, locally aggressive tumor that is often challenging to treat. When complete resection is not possible, curettage with or without adjuvants is the most common treatment. The high frequency of local recurrence and risk of injury to adjacent structures can limit this surgical approach, especially with skull and spine lesions., Case Description: We report 2 cases of axial skeleton GCTs, 1 in the skull of a 58-year-old woman in whom operative management failed, who experienced local recurrence, and 1 in the cervical spine of an 8-year-old girl that grew extracompartmentally to surround her brachial plexus. Both patients were referred to us because of the surgically challenging nature of their tumors. After completion of the same percutaneous doxycycline sclerotherapy protocol previously described for aneurysmal bone cysts (ABCs), both patients were considered cured and were able to return to normal activities without loss of pretreatment function. After 4 and 10 years of follow-up, respectively, there has been no tumor recurrence in either patient., Conclusions: We successfully treated 2 patients with very challenging axial skeleton GCTs using a percutaneous doxycycline sclerotherapy protocol previously shown to have success with ABCs. We believe that this minimally invasive procedure should be considered a potential alternative treatment for GCTs, especially axial skeleton lesions, which may not be easily approached with standard surgical techniques., Competing Interests: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2019 The Author(s).)