Invasive amoebiasis is rarely seen in human immunodeficiency virus (HIV)-infected individuals, even in endemic areas. By contrast, cytomegalovirus (CMV) disease is recognized as a major clinical problem in acquired immunodeficiency syndrome patients. A 34-year-old HIV-infected man with amoeba colitis, disseminated Mycobacterium avian complex and CMV infection with cecum perforation, presented with the initial symptoms of fever, shortness of breath and painful sensation when swallowing. He was treated with fluconazole, trimethoprim-sulfamethoxazole and hydrocortisone under the impression of esophageal candidiasis and Pneumocystis jiroveci pneumonia. However, diarrhea and abdominal pain developed on day 6 of hospitalization. Invasive amoebiasis and CMV colitis was diagnosed after examination of colon pathological specimens. Emergent laparotomy was performed. Right hemicolectomy with double barrel ileostomy and colostomy was done due to perforation of the cecum. Iodoquinol was given, followed by metronidazole 14 days afterwards. He underwent closure of double barrel ileostomy and colostomy 5 months later. This case illustrates the diagnostic challenge of caring for acquired immunodeficiency syndrome persons with multiple illnesses and medication use. CMV infection, amoebic colitis and possibly corticosteroid may have played a role in colon perforation in our patient.