Breast carcinoma with osteoclastic giant cells (OGCs) is a rare entity characterized by an admixture of giant cells and malignant epithelial cells within an inflammatory and vascular stroma. Denosumab is a monoclonal antibody that targets the pathway for osteoclast formation and activation, indicated for the prevention of skeletal-related events in patients with bone metastases, as well as for the treatment of giant cell tumor of bone. We report a patient who presented with aggressive bone recurrence of breast cancer 12 years after her original diagnosis, showing a transformed histology that included multinucleated OGCs, and that was refractory to traditional therapy. Misdiagnosed with a tumor-to-tumor metastasis of breast cancer to a giant cell tumor of bone, she was treated with denosumab for her presumed primary bone disease and had a remarkable clinical and radiological response. To the best of our knowledge, this is the first report of breast cancer with OGCs occurring initially in a metastasis while absent in the original tumor and the first description of its successful treatment with denosumab. This case sheds light on the development of giant cells in the tumor microenvironment and suggests the potential use of denosumab in the management of cancers with giant cell elements.