Rationale: Accumulating evidence supports the hypothesis that the continuous host response to a persistent challenge can polarize the cytokine environment toward a Th2 cytokine phenotype, but the mechanisms responsible for this skewing is not clear. Objectives: We investigated the role of Toll-like receptor 9 (TLR9) in a Th2-driven pulmonary granulomatous response, initiated via the embolization of _{Schistosoma mansoni} eggs to the lungs of mice. Methods: Mice were intravenously injected with _{Schistosoma mansoni} eggs. Histological and flow cytometric analysis, cytokine measurement, adoptive transfer of bone marrow (BM)-derived dendritic cells (DCs), and in vitro T cell treatments with antigen-presenting cells (APCs) were examined. Measurements and Main Results: In comparison to WT mice, TLR9^-/- mice showed an increase in pulmonary granuloma size, augmented collagen deposition, an increase in the Th2 cytokine phenotype, impaired accumulation of DCs. BM-derived DCs, but not macrophages, recovered from animals with developed Th2-type lung granulomas promoted the production of type 2 cytokines from CD4⁺ T cells. Furthermore, BM-derived DCs from TLR9^-/- mice induced impaired Th1 cytokine and enhanced Th2 cytokine production by T cells, compared with DCs from WT mice. Macrophages from TLR9^-/- mice expressed a significantly higher alternatively activated (M2) phenotype characterized by increased “found in inflammatory zone-1” (FIZZ1) and Arginase-1 expression. The adoptive transfer of BM-derived DCs from syngeneic WT mice into TLR9^-/- mice, restored the granuloma phenotype seen in WT mice. Conclusions: These studies suggest that TLR9 plays an important mechanistic role in the maintenance of the pulmonary granulomatous response.