Eight cases of leiomyosarcoma with osteoclast-like giant cells, arising in deep soft tissue, and that mimicked closely the “giant cell variant of malignant fibrous histiocytoma (MFH),” have been studied morphologically and immunohistochemically. The age of the patients ranged from 7 to 88 years (mean, 66.2 years; median, 74 years); five were female patients. Three lesions arose in the lower limbs, two in the buttock, and one each in the shoulder, chest wall, and the floor of the mouth. Follow-up in one case revealed a local recurrence and in two cases systemic metastases. All cases showed, at least focally, interwoven spindle cell fascicles, with the cytologic features of smooth muscle cells, as well as strong positivity for α-smooth-muscle actin, muscle actin, and desmin. The morphologically benign osteoclast-like giant cells expressed CD68 but failed to stain with myogenic markers. The association of leiomyosarcoma with prominent osteoclast-like giant cells is not as uncommon as generally believed, being evident in 8.7% of the deep-seated nonvisceral leiomyosarcomas that we have studied. These results provide good evidence for myogenic differentiation in at least a subset of those tumors with morphologic features currently classified as the giant cell variant of MFH. Considering that at least some other reported cases of giant cell MFH appear to be a variant of extraskeletal osteosarcoma, we would suggest that lesions with this distinctive pattern should be more carefully classified according to their apparent line of differentiation.