The inositol-requiring enzyme 1α (IRE1α) is a serine-threonine kinase that plays crucial roles in activating the unfolded protein response. Studies suggest that IRE1α is activated during thymic T cell development and in effector CD8(+) T cells. However, its role in regulating T helper cell differentiation remains unknown. We find that IRE1α is up-regulated and activated upon CD4(+) T cell activation and plays an important role in promoting cytokine IL-4 production. CD4(+) T cells from IRE1α KO mice have reduced IL-4 protein expression, and this impaired IL-4 production is not due to the altered expression of Th2 lineage-specific transcription factors, such as GATA3. Instead, IL-4 mRNA stability is reduced in IRE1α KO T cells. Furthermore, treatment of T cells with an IRE1α-specific inhibitor, 4μ8C, leads to a block in IL-4, IL-5, and IL-13 production, confirming the role of IRE1α in the regulation of IL-4. This study identifies a regulatory function for IRE1α in the promotion of IL-4 in T cells.