Prostaglandin E₂ (PGE₂) are known to be involved in inflammation and cancer. There are four subtypes of E-type prostanoid (EP) receptors, EP1 to EP4, for PGE₂. Among them, EP2 receptor and EP4 receptor are frequently confused because they are both coupled with Gs-protein. Although, we have previously shown that EP4 receptor is additionally coupled with Gi-protein. PGE₂ is metabolized to 15-keto-PGE₂ by the action of 15-hydroxy prostaglandin dehydrogenase. 15-keto-PGE₂ has been considered as an inactive form of PGE₂. However, we thought 15-keto-PGE₂ may activate EP receptor subtypes as biased agonist, since the only difference between PGE₂ and 15-keto-PGE₂ is a hydroxyl or a carbonyl functional group at position 15. Here we found that 15-keto-PGE₂ acts as a full agonist for EP2 receptor, while acting as a partial agonist for EP4 receptor. In addition, when compared to the affinity and efficacy, it was found that PGE₂ is tend to activate EP4 receptor, but when it is metabolized to 15-keto-PGE₂, it prefers to activate EP2 receptor. Thus, 15-keto-PGE₂ may not be just an inactive form of PGE₂, but may involve in the biological and physiological roles that need to be elucidated.