Gastrointestinal (GI) histoplasmosis is a rare manifestation of Histoplasma capsulatum (HC) infection. There are no reports of its cytologic diagnosis in the literature. A search of the cytology and surgical pathology files of the Methodist Hospital uncovered two cases of GI histoplasmosis and histiocytes within cytologic specimens. Papanicolaou-stained endoscopic brushings of an obstructing, apple-core, right colonic mass in a 58-year-old, heterosexual male revealed numerous vacuolated single cells interpreted as suspicious for signet ring cell carcinoma. The resected colon showed granulomatous inflammation with numerous histiocytes containing pale, oval yeasts of HC. The patient was subsequently found to be human immunodeficiency (HIV) positive; this was his first manifestation of the acquired immunodeficiency syndrome. The second patient was a 69-year-old, HIV-negative male with a fungating anal mass suspicious for squamous cell carcinoma. Direct smears showed oval histiocytes with intracellular yeasts of HC. Accurate diagnosis is crucial to patient management and therapy. Careful attention to the nuclear and cytoplasmic details of histiocytes and histiocytelike cells is important to avoid interpretive errors. Diagnostic pitfalls include signet ring cell adenocarcinoma, lymphoma, melanoma, goblet cell carcinoid, malakoplakia and such infections as mycobacteria, Entamoeba histolytica and Calymmatobacterium granulomatis. Ancillary studies, such as microbiologic cultures and immunohistochemical and histochemical staining, can be performed in the appropriate clinical setting.