Hypertrophic protein-losing gastropathy is a rare clinical entity of unknown etiology. Seventeen of 50 GI Units in The Netherlands, surveying their patient material, documented at least 1 positive case. Altogether, 40 patients (25 male and 15 female; mean age, 44.3 years) fulfilled the usually accepted criteria. Main complaints were epigastric pain (65%), asthenia (60%), anorexia (45%), weight loss 45%, edema (37.5%), and vomiting (37.5%). Hypoalbuminemia of < 35 g/l was found in 81%, and an abnormal enteric protein loss (51CrCl3) in 22 of 26 tested patients (85%). The mean basal acid output was 0.99 mmolH+/h. Stomach radiology in 35 patients showed giant folds mainly of the corpus mucosa; endoscopy confirmed the hypertrophy of the folds in all cases (in four confirmed by endosonography) and the presence of adherent mucus. Occasionally a concomitant gastric ulcer was found. Endoscopic biopsies were usually of limited value for the histologic diagnosis, mainly suggesting the possibility of hypertrophic gastropathy, excluding gastric cancer or lymphoma. In the follow-up 80% was treated with antacids, H2-receptor antagonists, mucosa-protectives, omeprazole, or combinations. No single agent appeared of major value. Eradication of Helicobacter pylori occasionally reduced symptoms. Twenty-two patients (55%) improved with or without medical therapy, during a mean follow-up of 7.6 years. Five patients (12.5%) underwent gastric surgery; four improved. In total, 26 patients (65%) improved, with partial or total regression of hypoalbuminemia. Eight patients died, three of gastric cancer, and five of cancers localized elsewhere.(ABSTRACT TRUNCATED AT 250 WORDS)