Bax is a Bcl-2 family member that promotes apoptosis but has paradoxical effects on lymphoma development in p53-deficient mice. To better understand the mechanism of Bax-induced lymphoma development, the effect of Bax levels, p53 status and Bcl-2 coexpression on lymphoma development were determined. In addition, DNA content and cytogenetics were performed on young (premalignant) Lck-Bax mice as measures of genetic instability. Bax promoted lymphoma development in p53-deficient mice in a dose-dependent manner. Bax expression also led to lymphoma development in both p53 +/- and +/+ animals. Ploidy analysis in mice prior to the onset of overt thymic lymphomas demonstrated that Lck-Bax transgenic mice were more likely to be aneuploid and demonstrate increased chromosome instability. With tumor progression, aneuploidy increased and Bax expression was maintained. Importantly, coexpression of Bcl-2 delayed lymphoma development in Lck-Bax transgenic mice. These data support a model in which increased sensitivity to apoptosis leads directly to chromosome instability in developing T cells and may explain a number of paradoxical observations regarding Bcl-2 family members and the regulation of cancer.