Enforced expression of growth factor independent 1 (Gfi-1), a transcription repressor induced by T cell activation and IL-4/Stat6 signaling, strikingly enhances Th2 cell expansion. Using conditionally Gfi1-deficient mice prepared for this study, we show that in vitro or in vivo deletion of this factor dramatically reduces Th2, but not Th1, cell expansion in response to IL-2. Both increased cell apoptosis and reduced cell proliferation resulted from Gfi1 deletion. IL-2-Stat5 signaling was partially reduced in Gfi1-deficient Th2 cells, but overexpression of Stat5 failed to restore normal Th2 expansion in these cells, suggesting that Gfi-1 also functioned downstream of, or in parallel with, Stat5 signaling. Reduced Th2 cell expansion in the absence of Gfi-1 was confirmed by the diminished frequency of IL-4-producing cells when these mice were infected with Schistosoma mansoni.