Prostaglandin E₂ (PGE₂), a major COX metabolite, plays important roles in several facets of tumor biology. We characterized the contribution of the PGE₂ EP2 receptor to cancer-associated immune deficiency using EP2^–/– mice. EP2^–/– mice exhibited significantly attenuated tumor growth and longer survival times when challenged with MC26 or Lewis lung carcinoma cell lines as compared with their wild-type littermates. While no differences in T cell function were observed, PGE₂ suppressed differentiation of DCs from wild-type bone marrow progenitors, whereas EP2-null cells were refractory to this effect. Stimulation of cells in mixed lymphocyte reactions by wild-type DCs was suppressed by treatment with PGE₂, while EP2^–/–-derived DCs were resistant to this effect. In vivo, DCs, CD4⁺, and CD8⁺ T cells were significantly more abundant in draining lymph nodes of tumor-bearing EP2^–/– mice than in tumor-bearing wild-type mice, and a significant antitumor cytotoxic T lymphocyte response could be observed only in the EP2^–/– animals. Our data demonstrate an important role for the EP2 receptor in PGE₂-induced inhibition of DC differentiation and function and the diminished antitumor cellular immune responses in vivo.