Technical Abstract: IL-4 and IL-13 promote gastrointestinal worm expulsion through effects on non-lymphoid cells, such as intestinal smooth muscle cells. The roles of Stat6 in IL-4, IL-13, and parasitic nematode-induced effects on small intestinal smooth muscle contractility were investigated in BALB/c WT and Stat6-deficient mice treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or IL-13 for seven days. Separate groups of mice were infected with Nippostrongylus brasiliensis or drug-cured of an initial Heligmosomoides polygyrus infection and later re-infected. Infected mice were studied at 9 and 12 days after inoculation. Segments of jejunum were suspended in an organ bath and responses to nerve stimulation and to acetylcholine and substance P in the presence and absence of tetrodotoxin were determined. Both IL-4 and IL-13 increased smooth muscle responses to nerve stimulation in wild type mice, but the effects were greater in IL-13 treated mice and were absent in IL-13 treated Stat6 deficient mice. Similarly, hyper contractile responses to nerve stimulation in Heligmosomoides polygyrus and Nippostrongylus brasiliensis infected mice were dependent, in part, on Stat6. IL-13, Heligmosomoides polygyrus and Nippostrongylus brasiliensis, but not IL-4, increased contractility to acetylcholine by mechanisms that involved Stat6 and enteric nerves. These studies demonstrate that both IL-4 and IL-13 promote intestinal smooth muscle contractility, but by different mechanisms. Differences in these effects correlate with differences in the relative importance of these cytokines in the expulsion of enteric nematode parasites.