Gastrointestinal stromal tumors (GISTs) are a heterogeneous group of mesenchymal tumors with a wide spectrum of histologic features and consistent expression of c-Kit. We describe an 85-year-old woman who presented with left lower quadrant abdominal pain and was subsequently diagnosed as having a malignant GIST. The tumor was composed of short fascicles of spindle cells. In addition to the presence of tumor giant cells, the tumor also demonstrated many osteoclast-like giant cells, a feature that has not been previously described in the literature. These giant cells expressed histiocytic markers CD68 and alpha(1)-antitrypsin but not c-Kit, a marker for GISTs. Electron microscopy showed no features of smooth muscle differentiation in the giant cells. The possible origin of the osteoclast-like giant cells is discussed in the context of immunohistochemical and ultrastructural characteristics.