TNF-related apoptosis-inducing ligand (TRAIL) is currently considered a promising target for developing anti-cancer therapies. Accumulating evidences have now shown that oxidative stress is involved in the TRAIL-mediated cell death. The peroxiredoxins (PRDXs) are a ubiquitous family of proteins involved in protection against oxidative stress through the detoxification of cellular peroxides. Here we demonstrated that endogenous expression of PRDX4 was significantly decreased by TRAIL at the transcriptional level. In addition, overexpression of PRDX4 dramatically suppressed TRAIL-induced apoptosis. Taken together, these data for the first time suggested that TRAIL suppressed the PRDX4 gene at the transcriptional level and that downregulation of PRDX4 might facilitate cell death induced by TRAIL.