OBJECTIVE To assess the effect of orally administered type II collagen (CII) in antigen-induced arthritis (AIA). METHODS Arthritis was induced in Lewis rats by immunization with methylated bovine serum albumin (mBSA) in Freund's complete adjuvant, followed by an intraarticular injection of mBSA 2 weeks later. Different doses of CII, mBSA, and an unrelated control protein, keyhole limpet hemocyanin (KLH), were orally administered 5 times over several days prior to the induction of arthritis. Ankle joint swelling and delayed-type hypersensitivity (DTH) responses were measured. RESULTS Joint swelling was significantly reduced at a dose of 3 micrograms and 30 micrograms of CII, but not at 300 micrograms. The most prominent suppression of AIA was observed when rats were fed 10 mg of mBSA, whereas oral KLH had no effect. DTH responses were significantly reduced in the mBSA-fed rats, but not in rats that were fed CII or KLH. CONCLUSIONS Oral CII can suppress arthritis in an animal model in which immunity to collagen does not play a role. The effect is dose dependent and occurs at lower doses of CII. These results demonstrate the biologic relevance of bystander suppression associated with oral tolerance, and the potential use of this approach to treat human inflammatory joint disease.