BACKGROUND: Peptides of the trefoil factor family (TFF1, TFF2 and TFF3) are cosecreted with mucus from mucus-producing cells in most organ systems and are believed to interact with mucus to form high-viscosity stable gel complexes. In the gastrointestinal tract, they sustain the mucosal barrier, and both injected and orally administered TFF peptide have protective and healing functions in the gastric mucosa. AIM: To investigate the possible treatment effect of luminally and parenterally administered TFF peptides in experimental colitis in rats. METHODS: Colitis was induced by administration of 5% dextran sodium sulphate in the drinking water or by one intraperitoneal injection of mitomycin C, 3.75 mg/kg. TFF peptides were administered as subcutaneous injections or directly into the lumen via a catheter placed in the proximal colon. Treatments were saline, TFF2, TFF3 monomer or TFF3 dimer 5 mg/kg twice per day throughout the study [dextran sulphate sodium (DSS)] or from day 4 to 7 (mitomycin C). Colitis severity was scored in a stereomicroscope and histologically. RESULTS: Luminal treatment with TFF3 in its dimeric form significantly improved the colitis score in both colitis models, whereas TFF2 had positive effect only in DSS-induced colitis. The TFF3 monomer was without any effects in both models. Treatment effect was most pronounced in the middle part of the colon, closest to the tip of the catheter. Injected TFF peptides, especially the TFF3 monomer, aggravated the colitis score in both colitis models. CONCLUSIONS: Intracolonic administration of TFF3 dimer and TFF2 improves experimentally induced colitis in rats. The TFF3 monomer has no effect. Parenteral administration of TFF peptides aggravates the colitis especially the TFF3 monomer.