Mice lacking both the p110γ and p110δ isoforms display severe impairment of thymocyte development. Here, we show that this phenotype is recapitulated in p110γ^−/−/p110δ^D910A/D910A (p110γ^KOδ^D910A) mice where the p110δ isoform has been inactivated by a point mutation. Moreover, we have examined the pathological consequences of the p110γδ deficiency, which include profound T-cell lymphopenia, T-cell and eosinophil infiltration of mucosal organs, elevated IgE levels, and a skewing toward Th2 immune responses. Using small-molecule selective inhibitors, we demonstrated that in mature T cells, p110δ, but not p110γ, controls Th1 and Th2 cytokine secretion. Thus, the pathology in the p110γδ-deficient mice is likely to be secondary to a developmental block in the thymus that leads to lymphopenia-associated inflammatory responses.