We explored the function of the intestine's mucosal barrier to foreign antigen entry in Crohn's disease. Macroscopically and microscopically uninvolved areas of the small intestines of patients with Crohn's disease were examined. We studied 27 endoscopic biopsy samples from 17 patients with Crohn's disease and 14 samples from nine controls. The absorption and degradation of horseradish peroxidase (molecular weight 40,000 Da) were studied in Ussing chambers. The absorption of intact horseradish peroxidase was significantly increased in patients with moderate or severe Crohn's disease: 271 (95% confidence interval 119-616) ng/hr/cm2, but not in those with slight disease activity: 42 (18-98), compared with controls: 45 (32-64); F = 10.90, P = 0.0002. The transport rates of degraded horseradish peroxidase were comparable in the Crohn's disease samples and controls. Our results indicate that enhanced absorption of macromolecules is associated with clinical activation of Crohn's disease, and impairment of the mucosal barrier function is a secondary phenomenon in Crohn's disease.