Though it has been shown that TGF-β1 directs B cells to switch to IgA in vitro, no studies have assessed TGF-β1 effects on mucosal vs systemic immunity in vivo. When the B cell functions of TGF-β1 gene-disrupted (TGF-β1−/−) mice were analyzed, significantly decreased IgA levels and increased IgG and IgM levels in serum and external secretions were observed. Further, analysis of Ab forming cells (AFC) isolated from both mucosal and systemic lymphoid tissue showed elevated IgM, IgG, and IgE, with decreased IgA AFC. A lack of IgA-committed B cells was seen in TGF-β1−/− mice, especially in the gastrointestinal (GI) tract. Splenic T cells triggered via the TCR expressed elevated Th2-type cytokines and, consistent with this observation, a 31-fold increase in serum IgE was seen in TGF-β1−/− mice. Thus, uncontrolled B cell responses, which include elevated IgE levels, a lack of antiinflammatory IgA, and an excess of complement-binding IgG and IgM Abs, will promote inflammation at mucosal surfaces in TGF-β1−/− mice and likely contribute to pulmonary and GI tract lesions, ultimately leading to the early death of these mice.