A hallmark of carcinogenesis is resistance to cell death. However, recent studies indicate that Bax expression increased apoptosis and promoted oncogenesis. In this study, we hypothesized that Bax promotes tumor formation by increasing chromosomal instability (CIN). Consistent with this hypothesis, spectral karyotype analysis (SKY) of lymphomas derived from Lck-Bax38/1 mice were consistently aneuploid. To determine if CIN precedes tumor formation, quantitative cytogenetic analysis, SKY analysis, and quantitative centrosome staining were done on thymocytes from young premalignant mice. Between 6 and 10 weeks of age, thymi from Bax-expressing mice (either p53+/+ or p53−/−) had an increased percentage of aneuploid cells as well as an increase in cells with supernumerary centrosomes. For 3- to 6-week-old mice, Bax expression increased aneuploidy and supernumerary centrosomes in p53−/− mice but not in p53+/+ animals. Importantly, both aneuploidy and supernumerary centrosomes were attenuated by Bcl-2. Remarkably, SKY analysis showed multiple independent aneuploid populations in the p53−/− Bax-expressing mice between 3 and 6 weeks of age. These results indicate that oligoclonal aneuploidy and supernumerary centrosomes are early hallmarks of Bax-induced lymphoma formation and support a novel link between the Bcl-2 family and CIN. The data provide an attractive model for the paradoxical effects of the Bcl-2 family on carcinogenesis that have been observed in multiple studies of both humans and mice. [Cancer Res 2007;67(17):8081–8]