Primary extraskeletal epithelial neoplasms containing osteoclast-like giant cells (OGCs) are rare. We herein describe a case of adenosquamous carcinoma that developed in the endometrium together with non-neoplastic OGCs. The patient was a 72-year-old woman who underwent radical hysterectomy with salpingo-oophorectomy and lymph node dissection after being diagnosed with uterine cancer. Histologically, the tumor was found to be an adenosquamous carcinoma containing a large number of OGCs and mononuclear cells (MNCs) that had infiltrated into the stroma. Immunohistochemically, the OGCs and MNCs stained strongly positive for KP-1 and alpha-1-antichymotrypsin, and negative for the epithelial markers epithelial membrane antigen (EMA) and cytokeratins. These findings suggest that the OGCs and MNCs in this patient's tumor originated from monocytes/histiocytes, and most likely developed as part of the stromal reaction to the neoplasm.