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The formation of multinucleated giant cells (MGCs) in an in vivo model of pulmonary inflammation was investigated to determine whether these cells are the result of a dominant T helper (Th) 1 or Th2 cytokine environment. We report that knockout (KO) mice with a disrupted interleukin (IL)-12 p40 gene exposed to the helminth Schistosoma mansoni had abundant and very large MGCs (> 50 μm) in their lungs concurrent with extensive eosinophilia and a population of large macrophages. Many of the MGCs and macrophages appeared to have phagocytosed eosinophils as part of a clearance process. The KO mice also had a strongly polarized Th2 immune response as judged by elevated levels in the lungs of messenger RNA (mRNA) transcripts for IL-4, IL-5, IL-6, and IL-13, but decreased levels of mRNA for interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). In addition, cells recovered by bronchoalveolar lavage from the airways of these mice secreted a Th2-biased profile of cytokines upon restimulation in vitro with parasite antigen. In contrast, wild-type C57BL/6 or KO mice treated with recombinant IL-12 had a polarized Th1 phenotype with elevated levels of IFN-γ and TNF-α mRNA in the lungs, and an airway cell population that secreted abundant IFN-γ. Very few MGCs were detected in these mice, and there was an absence of pulmonary eosinophilia. We conclude that the formation of MGCs in our model is promoted in the absence of IL-12 and is linked instead to the abundance of Th2 cytokines, notably IL-4 and IL-13.