Treatment of carcinoma cell lines with 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-&ggr;, has been reported to induce apoptosis and/or inhibit proliferation. In this study, we investigated the cytotoxic effect and the action mechanisms of 15d-PGJ2in a thyroid papillary cancer cell line, CG3. The results indicate that 15d-PGJ2caused cytotoxicity and increased the amount of intracellular reactive oxygen species (ROS) in these cells. Mitochondrial oxidative phosphorylation inhibitors (carbonyl cyanidem-chloro-phenylhydrazone, oligomycin, cyclosporin A and rotenone), NADPH oxidase inhibitor (diphenyleneiodonium), xanthine oxidase inhibitor (allopurinol) and NO synthase inhibitor (N-monomethyl-l-arginine acetate) did not reduce the generation of ROS. However, catalase,N-acetyl-cysteine and the iron chelator desferri-oxamine decreased the intracellular ROS of 15d-PGJ2-treated CG3 cells. Furthermore, 15d-PGJ2enhanced the accumulation of iron in the CG3 cells. These data suggest that 15d-PGJ2induces the generation of ROS by enhancing the accumulation of intracellular iron and that the increased oxidative stress may cause apoptosis of CG3 cells.