We report six cases of toxic megacolon in patients with human immunodeficiency virus (HIV). One case, at an early stage of HIV infection, mimicked a severe attack of Crohn's disease, with a negative search for infectious agents. Subtotal colectomy was successfully performed with an uneventful postoperative course. The five other cases concerned patients with acquired immunodeficiency syndrome at a late stage of immunodeficiency. They were related to Clostridium difficile or cytomegalovirus (CMV) intestinal infection in two and three patients, respectively. One case of CMV colitis presented macroscopically and histologically as pseudomembranous colitis. Emergency subtotal colectomy, performed in the first four patients with acquired immunodeficiency syndrome was followed by a fatal postoperative outcome. The last patient treated conservatively by colonoscopic decompression, in association with anti-CMV therapy, had a favorable short-term outcome. From the experience of our series and data from the literature, we discuss the best diagnostic and therapeutic approach to toxic megacolon in patients with HIV.