The usual manifestation of histoplasmosis is in the form of respiratory illness. We report the case of a 67-year-old man who presented with chronic diarrhea and did not respond to the conventional treatment, including that for Clostridium difficile. He was found to have isolated colonic histoplasmosis infection, which was treated with itraconazole. There was no evidence of any disseminated disease. His only immunocompromised state was end-stage renal disease, for which he was on chronic hemodialysis. Although it is well documented as a part of disseminated histoplasmosis, our extensive review of the literature did not reveal any reported case of isolated colonic histoplasmosis in a patient on hemodialysis.