Thirty-five rheumatoid arthritis (RA) patients and 27 healthy volunteers were enrolled in the study. Regula-tory T (Treg) cell numbers were significantly reduced in RA patients. RA Treg cells exhibited an impaired capacity to inhibit proliferation and cytokine secretion of autologous T effector (Teff) cells. However, the crossover experiments further indicated that this impaired suppression was due to resistance of Teff cells but not to an intrinsic defect of Treg cells in RA patients. RA Teff cells showed a higher expression of membrane tumor necrosis factor-related apoptosis-inducing ligand and secreted more soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL could induce apoptosis in Treg cells. Neutralization of TRAIL restored the regulation of Teff by Treg in RA patients. In summary, our data suggest that reduced peripheral Treg cell numbers and an increased resistance of Teff cells to suppression by Treg cells were present in RA patients, and TRAIL may be an underlying mechanism for the impaired regulation of Teff cells by Treg cells.