Background. Exposure of renal tubular epithelial cells (TEC) to IFN-/TNF- leads to Fas/FasL mediated self-injury, which contributes to allograft rejection. Indoleamine 2,3 dioxygenase (IDO) converts tryptophan to N-formyl-kynurenine and contributes to immune privilege in tissues by increasing Fas-mediated T cell apoptosis. However, renal expression of IDO and its role in promoting Fas-mediated TEC death have not been examined. Methods. IDO expression was analyzed by RT-PCR and Western blot. Apoptosis was measured by FACS analysis and TUNEL. Results. We demonstrate that functional IDO is expressed in TEC and is increased by IFN-/TNF- exposure. Increased IDO activity promotes TEC apoptosis, while inhibition of IDO by its specific inhibitor 1-methyl-d-tryptophan (1-MT) attenuates IFN-/TNF--mediated TEC apoptosis and augments TEC survival. Transgenic expression of IDO resulted in increased TEC apoptosis in the absence of pro-inflammatory cytokine exposure, supporting a central role for IDO in TEC injury. Inhibition of IDO-mediated TEC death by a caspase-8 specific inhibitor (Z-IETD-FMK), as well as absence of IDO effect in Fas deficient and FasL deficient TEC supports a Fas/FasL dependent, caspase-8 mediated mechanism for IDO enhanced TEC death. Conclusion. These data suggest that renal IDO expression may be deleterious during renal inflammation as it enhances TEC self-injury through Fas/FasL interactions. Thus, attenuation of IDO may represent a novel strategy to promote kidney function following ischemia and renal allograft rejection.