Defects in antitumor immune responses have been associated with increased release of prostaglandin E₂ (PGE₂) as a result of overexpression of cyclooxygenase (COX)-2 by tumors. In this report, we examine the effects of PGE₂ on antitumor CD8⁺ T-cell responses generated both by cross-presenting dendritic cells and by direct priming by tumor cells. Our data show that PGE₂ inhibits dendritic cell maturation, resulting in the abortive activation of naive CD8⁺ T cells, and is dependent on interleukin-10 production by dendritic cells. Interaction of tumor cells with naïve CD8⁺ T cells in the presence of PGE₂ in vitro results in the induction of CD8⁺ CD28⁻ T cells, which fail to proliferate or exhibit effector function. In vivo, overexpression of COX-2 by tumor cells results in a decrease in number of tumor-infiltrating dendritic cells and confers the ability of tumor cells to metastasize to the tumor draining lymph nodes. [Cancer Res 2008;68(18):7520–9]