It has been assumed that prostaglandin (PG)I 2 signaling contributes to the negative growth control of lung cancer cells; however, the mechanism remains unresolved. PGI 2 functions through a cell surface G protein-coupled receptor (prostaglandin I2-binding receptor, IP) and also exerts an effect by interacting with a nuclear hormone receptor, peroxisome proliferator-activated receptor d (PPARd). We found that PPARd was a key molecule of PGI 2 signaling to give negative growth control of lung cancer cells (A549), using carbarprostacyclin, a PGI 2 agonist for IP and PPARd, and L-165041, a PPARd agonist. Furthermore, PPARd-induced cell growth control was reinforced by the inhibition of cyclooxygenase. These results suggest that PPARd activation under the suppression of PG synthesis is important to regulate lung cancer cell growth.