Tropical pulmonary eosinophilia (TPE) is a severe asthmatic syndrome of lymphatic filariasis, in which an allergic response is induced to microfilariae (Mf) in the lungs. Previously, in a murine model for TPE, we have demonstrated that recombinant interleukin-12 (IL-12) suppresses pulmonary eosinophilia and airway hyperresponsiveness (AHR) by modulating the T helper (Th) response in the lungs from Th2- to Th1-like, with elevated gamma-interferon (IFN-) production and decreased IL-4 and IL-5 production. The present study examined the immunomodulatory roles of IL-4 and IFN- in filaria-induced AHR and pulmonary inflammation using mice genetically deficient in these cytokines. C57BL/6, IL-4 gene knockout (IL-4^/), and IFN-^/ mice were first immunized with soluble Brugia malayi antigens and then inoculated intravenously with 200,000 live Mf. Compared with C57BL/6 mice, IL-4^/ mice exhibited significantly reduced AHR, whereas IFN-^/ mice had increased AHR. Histopathologically, each mouse strain showed increased cellular infiltration into the lung parenchyma and bronchoalveolar space compared with naïve animals. However, consistent with changes in AHR, IL-4^/ mice had less inflammation than C57BL/6 mice, whereas IFN-^/ mice had exacerbated pulmonary inflammation with the loss of pulmonary architecture. Systemically, IL-4^/ mice produced significantly higher IFN- levels compared with C57BL/6 mice, whereas IFN-^/ mice produced significantly higher IL-4 levels. These data indicate that IL-4 is required for the induction of filaria-induced AHR, whereas IFN- suppresses AHR.