Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E₂ (PGE₂) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4^−/−) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4^−/− mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE₂-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells.