Cord colitis syndrome (CCS) is a recently described diarrheal illness of uncertain pathogenesis that affects recipients of umbilical cord blood transplant and is associated with negative cultures. CCS exhibits a peculiar histopathologic appearance, as it commonly manifests as granulomatous inflammation involving the upper and lower gastrointestinal tract, with features of chronicity in the colon. Importantly, the treatment for CCS differs from that for acute graft-versus-host disease, which is commonly in the clinical differential diagnosis: CCS responds to antibiotic treatment, whereas acute graft-versus-host disease responds to immunosuppression. We describe here the case of a 36-year-old woman with a history of acute myeloid leukemia who developed refractory diarrhea after cord blood transplant. Endoscopic biopsies of the stomach and colon revealed granulomatous inflammation, consisting of scattered ill-defined aggregates of epithelioid histiocytes, with associated mild neutrophilic inflammation and mildly increased epithelial cell apoptosis. In the colon, the granulomatous inflammation was associated with surface epithelial injury (including surface erosions) and contained occasional multinucleated epithelioid giant cells. Paneth cell metaplasia was present in the distal colon, but crypt architecture was preserved, and there was no basal lymphoplasmacytosis. Special stains and immunohistochemical stains for infectious organisms were negative. A diagnosis of CCS was made, and the patient promptly responded to treatment with ciprofloxacin and metronidazole. We present this case to raise awareness among pathologists of this newly described entity, in order to facilitate its timely diagnosis and treatment.