The local environment in which dendritic cells (DC) differentiate is important for the acquisition of their immunostimulatory properties. Since prostaglandin D₂ (PGD₂), a major prostanoid produced during inflammatory reactions, is involved in the control of immune responses, its effect on the differentiation and functions of human monocyte‐derived dendritic cells (MDDC) was studied. We show that DC differentiated in the presence of PGD₂ (PG/DC) have an unusual phenotype, with modifications in the expression of molecules involved in antigen (Ag) capture and presentation, leading to higher endocytic and Ag‐processing activities. However, under conditions that necessitated Ag processing and presentation, PG/DC have an impaired ability to stimulate naive T cells, whereas superAg‐pulsed DC efficiently promote their proliferation. Upon lipopolysaccharide or TNF‐α/IL‐1β stimulation, PG/DC phenotypically mature but produce abnormal amounts of immunoregulatory cytokines (decreased IL‐12p70/IL‐10 ratio). Moreover, mature PG/DC fail to up‐regulate the chemokine receptor CCR7 and show an impaired migration towards its ligand CCL19. Finally, PG/DC favor the differentiation of naive T cells toward Th2 cells, an effect dependent on IL‐10 and inducible costimulator ligand expression by DC. Most of the herein described effects of PGD₂ on MDDC can be reproduced, usually with a higher efficacy, with a selective D prostanoid receptor (DP)1, but not DP2, agonist. Taken as a whole, these results demonstrate that PGD₂ impacts DC differentiation and functions, and extend the concept that it exerts important roles in immunity.