Cronkhite-Canada syndrome is a rare protein-losing enteropathy, classically characterized by ectodermal changes and gastrointestinal polyposis. The etiology remains obscure but immune dysregulation may be important. The diagnosis of Cronkhite-Canada syndrome in the upper gastrointestinal tract is challenging, frequently resulting in delayed patient management. In this study, we described the initial clinical presentations, upper gastrointestinal endoscopic appearances, clinical follow-up, and histologic diagnoses in 7 patients who were subsequently diagnosed with Cronkhite-Canada syndrome. Histology slides were reviewed, and IgG4 immunohistochemical analysis was performed. The most common initial endoscopic impressions were antral malignancy and gastric infection, but gastroduodenal polyposis was not described. On histologic review, the main findings in the gastric mucosa were a prominent mucosal edema, a mixed inflammatory infiltrate rich in eosinophils, and architectural changes with gland dilatation and withering. In the duodenal mucosa, total or subtotal duodenal villous atrophy, inflammation, crypt distortion, and increased apoptotic bodies were the most common features. Three patients died of the disease, and 4 patients were asymptomatic at a mean follow-up of 3.5 years. No intestinal malignancy had been diagnosed. In 2 patients foci of dysplasia in colonic polyps were identified. In only 1 patient, a significant increase in IgG4-positive plasma cells was observed in a colonic polyp. In summary, we found that patients with Cronkhite-Canada syndrome have histologic features commonly found in other immune disorders of the gastrointestinal tract that may help in establishing the diagnosis and further supports the hypothesis that Cronkhite-Canada syndrome may represent an immune dysregulation syndrome, different from IgG4-related disease. Copyright