We report the case of a patient with Cronkhite-Canada syndrome (CCS) successfully treated with combination medical therapy. This rare, noninherited gastrointestinal polyposis syndrome is associated with characteristic ectodermal abnormalities. The etiology and pathogenesis of CCS are not known. No medical therapy has been shown to be consistently effective, and the disease is usually fatal. The patient described herein was successfully treated with a novel combination regimen consisting of H1- and H2-receptor antagonists, cromolyn sodium, prednisone, and suppressive antibiotics. This regimen has resulted in sustained improvement in symptoms, and follow-up endoscopy has shown regression of the diffuse polyposis. Our patient's response to such therapy may provide insight into the optimal treatment for CCS.