Chronic peritoneal dialysis results in fibrosis of the peritoneal membrane, which leads to progressive reduction in dialytic efficacy. It was recently shown that the intraperitoneal administration of glycosaminoglycans (GAGs) improves the efficiency of peritoneal dialysis in CAPD patients. To verify whether the favorable effects of GAGs are purely functional or involve a morphological amelioration of the peritoneal membrane structure, a study was carried out in an animal model of plasticizer-induced peritoneal fibrosis. Rats, in which chronic renal failure had been induced by subtotal nephrectomy, received either placebo, plasticizers (i.p.), or GAGs (s.c.), or plasticizers (i.p.) and GAGs (s.c.). Urea dialysate-to-plasma equilibrium, urea and albumin peritoneal clearance, and glucose reabsorption were determined. The peritoneal membrane was evaluated morphometrically and histologically. In plasticizer-treated animals, peritoneal function tests and morphology were dramatically deranged. On the contrary, the subcutaneous administration of GAGs in plasticizer-treated rats maintained the peritoneal physiology and normal structure. The subcutaneous administration of GAGs protects peritoneal functions by affecting the remodeling of the peritoneum, rather than by a purely functional or simple mechanical effect.