T cell receptor α chain–deficient (TCR-α^−/−) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4⁺TCR-ββ (CD4⁺ββ) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4⁺ββ T cells, we treated TCR-α^−/− mice with anti–IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-α^−/− mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti–IL-4 mAb–treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab–treated mice. Although TCR-α^−/− mice treated with either specific or mock Ab developed CD4⁺ββ T cells, only those treated with anti–IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon γ–specific expression. These findings suggest that IL-4–producing Th2-type CD4⁺ββ T cells play a major immunopathological role in the induction of IBD in TCR-α^−/− mice, a role that anti–IL-4 mAb inhibits by causing Th2-type CD4⁺ββ T cells to shift to the Th1 type.