Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are members of the herpesvirus family and common causes of viral infection in humans. CMV infection of the gastrointestinal tract occurs mainly in immunocompromised individuals, on the other hand EBV infection and reactivation involving the gastrointestinal tract is very rare. A 56-year-old man was diagnosed with severe aplastic anemia and treated with antithymocyte globulin (ATG) and cyclosporine (CSP). After 2 years of ATG/CSP therapy, he suddenly started passing bloody diarrhea and developed a high fever despite CSP treatment. Endoscopic features included severe edema and multiple superficial ulcers; the patient was initially diagnosed with severe colitis resembling inflammatory bowel disease (IBD). However, his symptoms did not resolve with steroid treatment. Immunohistochemical analysis of samples obtained from a second colonoscopy showed cells positive for CMV, and in situ hybridization revealed EBV-encoded small RNA-1-positive cells. Additionally, the patient's serum was positive for C7-HRP, and both blood and colon tissues were positive for EBV DNA, which was detected using PCR analysis. We finally diagnosed the patient with colitis associated with reactivation of both CMV and EBV. The patient remains diarrhea-free after 1.5 years with scheduled globulin treatment and after cessation of immunosuppressive drug therapy. To our knowledge, this is the first reported case of an immunodeficient patient with severe hemorrhagic colitis that was associated with reactivation of both EBV and CMV, and whose endoscopic findings mimicked IBD.