Histoplasma capsulatum is an important pathogen that is the most commonly diagnosed endemic mycosis in the gastrointestinal tract of immunocompromised hosts. Failure to recognize and treat disseminated histoplasmosis in AIDS patients invariably leads to death. Gastrointestinal manifestations frequently involve the terminal ileum and cecum, and depending on the layer of bowel wall involved present as bleeding, obstruction, perforation, or peritonitis. Because they can be variable in appearance, they may be mistaken for Crohn's disease or malignant tumors. Four distinct pathologic patterns of GI histoplasmosis have been described that all have differing clinical presentations. We report a case of a non-AIDS patient who presented with a near-obstructing colonic mass suspicious for advanced malignancy but was found to have histoplasmosis on final pathology. The patient underwent successful operative resection, systemic antifungal therapy, and extensive workup for immunosuppressive disorders, which were negative. The patient was from an area in Mexico known to be endemic for histoplasmosis. This is the first report of a colonic mass lesion occurring in a non-AIDS patient, and review of the worldwide literature regarding GI histoplasmosis reveals excellent long-term survival with aggressive therapy. We discuss the surgical and medical management of colonic histoplasmosis in this report.