To investigate the effects of altered collagen II (CII) peptide ligands in collagen-induced arthritis (CIA), CIA rats were subcutaneously injected with an altered CII263-272 peptide ligand (APL, 100, 10, and 1 microg/dose, six dose each, twice a week), which had been identified by us as an inhibitory effect on CII-specific T-cell activation in vitro in rheumatoid arthritis (RA). Clinical, radiographic, and histologic scores were evaluated. Serum level of interferon (IFN)-gamma was assessed by enzyme-linked immunosorbent assay, and the numbers of interleukin (IL)-4-producing cells in vitro in memory responses to the APL were determined by enzyme-linked immunospot. The results showed significantly reduced arthritis scores in CIA rats treated with 100 microg/dose of APL compared with those treated with phosphate buffered solution (PBS) and control peptide. The mean radiographic and histologic scores were also markedly lower in APL-treated CIA rats. On day 35 after immunization, a significantly lower level of IFN-gamma in serum was found in APL-treated rats, accompanied by increased numbers of IL-4-producing cells, indicating that APL treatment skewed the T helper (Th)1/Th2 balance toward Th2-type response in vivo. Altered CII263-272 peptide ligand immunization induces inhibition of CIA through a shift toward Th2-type response, suggesting that altered CII peptide might be a potential therapeutic target for RA.