There has been a prevailing perception that Th1 and Th2 immune responses induce antagonistic immune effector mechanisms during an infection. We investigated the role of the Th1 cytokine gamma interferon (IFN-gamma) and the Th2 cytokine interleukin-5 (IL-5) in murine filariasis infections with the rodent filarial nematode Litomosoides sigmodontis with regard to immune responses to the parasite. Earlier data showed an important role for IL-5 and IFN-gamma in effective immune responses to filarial infection. Therefore, in this study it was asked whether IL-5 and IFN-gamma act synergistically or antagonistically. Indeed, IL-5 as well as IFN-gamma knockout (KO) mice show a higher worm load than the wild-type controls. IFN-gamma/IL-5 double-KO mice had a significantly higher worm load than any of the single-KO mice, suggesting a synergism between IFN-gamma and IL-5 in controlling worm infection. Neutrophils are known to play an important role for the containment and encapsulation process of the worms. In infected IFN-gamma KO, IL-5 KO, and IFN-gamma/IL-5 double-KO mice, neutrophils were significantly reduced in chemotactic activity levels compared to controls. In addition, the level of phagocytosis activity of neutrophils from IFN-gamma/IL-5 double-KO mice was further decreased in comparison to that of the single-KO mice. Levels of tumor necrosis factor alpha, which is an important factor for neutrophil activation, were found to be reduced in macrophages from KO mice. In conclusion, these results argue for immune effector mechanisms in murine filarial infection that are dependent on both IFN-gamma and IL-5. Synergistic effects of the two cytokines may be mediated, at least in part, by neutrophils for the control of adult worms.