A rare spindle-cell pseudotumor caused by Mycobacterium avium-intracellulare (MAI) that mimics a mesenchymal tumor, was recently reported (7,14). We report on three such pseudotumors in patients with the acquired immunodeficiency syndrome (AIDS), two involving lymph nodes and one involving the bone marrow. In the course of investigating the first-encountered example of this tumor for evidence of smooth-muscle origin of the spindle cells, it was noted that these cells stained positively for desmin by immunoperoxidase techniques (IPX), as did a variety of other cytoskeleton filaments of all sizes. Electron microscopic examination of one of these lesions revealed spindle cells containing lysosomes and large numbers of microorganisms compatible with MAI but no filaments or organelles suggestive of smooth-muscle cells. Further studies revealed that the typical lesions produced by MAI in patients with AIDS, namely aggregates of histiocytes or individual histiocytes laden with organisms, rather than the expansile spindle-cell pseudotumor, also strain strongly for cytoskeleton filaments, as do M. tuberculosis and Mycobacterium leprae. Awareness of the existence of this unusual manifestation of MAI infection in AIDS patients and its desmin positivity can avoid misdiagnosis of a primary or metastatic smooth-muscle neoplasm. The cell of origin appears to be the histiocyte.