Two anaplastic thyroid carcinomas with osteoclast-like giant cells (OCL-GC) are reported. Light microscopically, one case resembled an aneurysmal bone cyst with cellular connective-tissue septae separating cavernous, blood-filled sinuses. The second case had sheets of anaplastic cells and a separate focus of papillary carcinoma without areas of transition. Multinucleate OCL-GC, pleomorphic mononuclear cells, and histiocytoid mononuclear cells with nuclei similar to those within the OCL-GC were seen in each case. With formalin-fixed, paraffin-embedded tissue, the majority of OCL-GC and histiocytoid mononuclear cells in both cases showed immunoreactivity using monoclonal antibodies to vimentin and KP-1, with the latter preparation directed against cells of monocytic/histiocytic lineage. Staining for keratin, epithelial membrane antigen, neuron-specific enolase, chromogranin, calcitonin, and thyroglobulin was negative in all cell types. Ultrastructural examination of one case showed two distinct types of mononuclear cells--one with morphologic characteristics similar to those of the OCL-GC, and another with pleomorphic nuclei and short cytoplasmic extensions joined by poorly formed desmosomes. The findings indicate that the anaplastic thyroid carcinomas studied represent poorly differentiated epithelial tumors infiltrated by reactive OCL-GC of monocytic/histiocytic lineage apparently derived from histiocytoid mononuclear cells via cellular fusion.