To assess in a multicenter double blind clinical trial the gastroenteroprotective effect of zinc acexamate (ZAC). 276 patients with rheumatic disease and history of peptic ulcer or intolerance to nonsteroidal antiinflammatory drugs (NSAID), and requiring treatment with these drugs were included. An initial normal endoscopy was needed for inclusion. Patients were treated with one NSAID (diclofenac, piroxicam, naproxen or ketoprofen) and one capsule (300 mg) of either ZAC (141 patients) or placebo (135 patients) at single nocturnal dose. After 28 days, patients underwent a clinical and endoscopic control. 26 patients withdrew from the trial (10 of ZAC and 16 of placebo) and 41 were lost to followup (22 of ZAC and 19 of placebo). Gastroduodenal mucosal damage was graded according to a modified Lanza score. The incidence of gastric ulcer was null with ZAC and 6.0% with placebo (6 cases) (p < 0.05). The incidence of duodenal ulcer was 0.9% with ZAC (1 case) and 6.0% with placebo (12 cases) (p < 0.001). Nine patients of ZAC group (8%) and 25 of placebo (25%) presented some gastric damage (p < 0.001), and 5 (5%) and 19 (19%) respectively presented some duodenal damage (p < 0.005). After treatment, 88% of patients treated with ZAC and 66% with placebo had a completely normal endoscopy (p < 0.0005). No major side effects were reported through the study. ZAC has shown to be effective and well tolerated for the prevention of NSAID induced gastroduodenal damage in patients with rheumatic disease at risk. The incidence of gastric and duodenal ulcers decreased in 92% (13 times the risk), when compared to placebo.