Caspase-2, one of the most evolutionarily conserved of caspases, has been implicated in maintenance of genomic stability and tumor suppression. Caspase-2 deficient mice develop normally but show premature ageing traits and when challenged by certain stressors, succumb to enhanced tumor development and/or aneuploidy. To test how caspase-2 protects against genomic instability, we developed an ex vivo system for aneuploidy where primary splenocytes from caspase-2 deficient mice were exposed to anti mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 deficiency leads to significantly enhanced aneuploidy and this is because of reduced cell death. Acute knockdown of caspase-2 recapitulated these results. Thus in the absence of caspase-2 an inhibition of death of cells with mitotic defects leads to aneuploidy. These results provide direct evidence that caspase-2 is necessary for deleting cells with mitotic aberrations.