The aim of this double-blind, randomized placebo-controlled trial was to evaluate whether sulglycotide prevents the onset of gastroduodenal mucosal injury in patients with rheumatic disease treated with nonsteroidal anti-inflammatory drugs (NSAIDs). One hundred patients, free from endoscopically detectable lesions of the gastroduodenal mucosa, affected either by rheumatoid arthritis or osteoarthritis, and candidates for NSAID therapy, were randomly allocated either to 200 mg sulglycotide three times daily (n = 50) or to an indistinguishable placebo (n = 50) for 4 weeks, together with standard NSAID administration (50 mg diclofenac three times daily (n = 50); 50 mg indomethacin three times daily (n = 50)). Upper gastrointestinal endoscopy was repeated at the end of the study. It was possible to evaluate 86 patients after treatment (sulglycotide = 42, placebo = 44); diclofenac = 45, indomethacin = 41). Six of 42 patients (14%) in the sulglycotide group and 15 of 44 (34%) in the placebo group had developed gastric or duodenal ulcerative lesions (p = 0.02). These data suggest that sulglycotide prophylaxis may be useful for the prevention of gastric and duodenal ulcer associated with NSAID therapy in rheumatic patients.