Graft-versus-host disease in the upper gastrointestinal tract presents with anorexia, vomiting, and abdominal discomfort. Because these symptoms are not specific, we have proposed that a diagnosis of upper GI GVHD requires histologic confirmation. However, the utility of upper endoscopy in the diagnosis of upper GI GVHD has not been examined. We report a retrospective analysis of 77 allogeneic bone marrow transplantation recipients who received simultaneous upper and lower GI tract biopsies. Upper GI GVHD was found in 44% of patients, of whom 59% also had a positive lower GI tract biopsy (P less than 0.001). Thirty-five percent of the patients with no clinical evidence of lower GI tract GVHD had symptomatic upper GI GVHD confirmed histologically. Patients with and without upper GI GVHD had no significant difference in their clinical symptoms or in their endoscopic findings. We found an association between upper GI and skin GVHD greater than stage I (P = 0.05), a trend to concordance between upper GI GVHD and clinical GVHD in the lower GI tract (P = 0.08), and with the overall clinical GVHD grade (P = 0.08) but no association with clinical liver involvement. Of these 77 patients, 16% had their treatment for acute GVHD changed to include systemic immunosuppression as a result of the upper GI endoscopic biopsy. In addition, 71% had other enteric pathology identified that required specific therapy. These data suggest that upper GI GVHD cannot be diagnosed accurately from its clinical presentation nor inferred from lower GI symptoms or from extraintestinal GVHD. Upper GI endoscopy with biopsy is an important tool in the diagnosis of intestinal GVHD.