We examined the role of TLR3 in Th2-driven pulmonary granulomatous disease, using wildtype (TLR3(+/+)) and TLR3 gene-deficient (TLR3(-/-)) mice in a well-established model of Schistosoma mansoni egg-induced pulmonary granuloma. The intravenous bolus injection of S. mansoni eggs into S. mansoni-sensitized TLR3(+/+) mice was associated with an increase in TLR3 transcript expression in alveolar macrophages and ex vivo spleen and lung cultures at day 8 after egg injection. Lungs from TLR3(-/-) mice showed an increase in granuloma size, greater collagen deposition around the granuloma, and increased Th2 cytokine and chemokine levels compared with similarly sensitized and challenged TLR3(+/+) mice. Macrophages from TLR3(-/-) mice exhibited an M2 phenotype characterized by increased arginase and CCL2 expression. Significantly greater numbers of CD4(+)CD25(+) T cells were present in the lungs of TLR3(-/-) mice compared with TLR3(+/+) mice at day 8 after egg embolization. Cells derived from granulomatous lung and lung draining lymph nodes of TLR3(-/-) mice released significantly higher levels of IL-17 levels relative to TLR3(+/+) cells. Thus, our data suggest that TLR3 has a major regulatory role during a Th2-driven granulomatous response as its absence enhanced immunopathology.