Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands are potential chemo-preventive agents. Many studies have shown that PPARy ligands induce apoptosis in various types of cancer cells including lung cancer cells. Some PPAR gamma ligands have been shown to downregulate c-FLIP expression and thus enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in some cancer cell lines. In the current study, we further show that PPARy ligands induced the expression of death receptor 5 (DR5) and increased DR5 distribution at the cell surface in addition to reducing c-FLIP levels in human lung cancer cells. These agents cooperated with TRAIL to enhance induction of apoptosis in human lung cancer cells. Both overexpression of c-FLIP and knockdown of DR5 abrogated PPARgamma ligand's ability to enhance TRAIL-induced apoptosis. Thus, it appears that not only c-FLIP downregulation but also DR5 upregulation contribute to PPARy ligand-mediated enhancement of TRAIL-induced apoptosis in human lung cancer cells. Both the PPARgamma antagonist GW9662 and silencing PPARgamma expression failed to diminish PPARgamma ligand-induced DR5 upregulation or c-FLIP downregulation, indicating that PPARy ligands modulate the expression of DR5 and c-FLIP through a PPARy-independent mechanism. Collectively, we conclude that PPARy ligands exert PPARy-independent effects on inducing DR5 expression and downregulating c-FLIP levels, leading to enhancement of TRAIL-induced apoptosis.