There is increasing evidence that dendritic cell (DC) immunogenicity is not only positively regulated by ligands of pattern recognition receptors, but also negatively by signals that prevent DC activation and full functional maturation. Depending on their activation status, DCs can induce either immunity or tolerance. In this study, we provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is a negative regulator of DC maturation and function. Sustained PPARγ activation in murine DCs reduced maturation-induced expression of costimulatory molecules and IL-12, and profoundly inhibited their capacity to prime naive CD4+ T cells in vitro. Using PPARγ-deficient DCs, generated by Cre-mediated ablation of the PPARγ gene, agonist-mediated suppression of maturation-induced functional changes were abrogated. Moreover, absence of PPARγ increased DC immunogenicity, suggesting a constitutive regulatory function of PPARγ in DCs. Adoptive transfer of PPARγ-activated Ag-presenting DCs induced CD4+ T cell anergy, characterized by impaired differentiation resulting in absent Th1 and Th2 cytokine production and failure of secondary clonal expansion upon restimulation. Collectively, our data support the notion that PPARγ is an efficient regulator of DC immunogenicity that may be exploited to deliberately target CD4+ T cell-mediated immune responses.