Cytomegalovirus (CMV) continues to be potentially the most important pathogen affecting organ transplant recipients. Severe gastrointestinal complications have been reported to occur in about 10% of renal transplant recipients, sometimes with dramatic presentations. We report the case of a 57-year-old CMV-seropositive woman with end-stage renal failure who developed CMV-related colonic multiple perforation 30 days after cadaveric CMV-positive renal transplantation. CMV pp65 antigenemia test and CMV-PCR had always been negative on all the weekly controls routinely performed in the postoperative period. Only after the sudden onset of this complication did the antigenemia and PCR become positive. The relationship between infection and perforation has been established beyond any doubt, as the histology of the resected colonic segment revealed florid CMV infection with evidence of typical inclusions in both macrophages and endothelial cells. Colonic perforations are often fatal in transplant recipients because of inability to contain the perforation, and only a rapid diagnosis and an aggressive surgical treatment can improve the prognosis.