Memory T cells are critical for the control of intracellular pathogens and require few signals for maintenance; however, erosion of established preexisting memory CD8(+) T cells has been shown to occur during infection with heterologous viral infections. We evaluated whether this also occurs during infection with various intracellular bacteria and what mechanisms may be involved. We demonstrate that erosion of established memory is also induced during infection of mice with various intracellular bacteria, such as Listeria monocytogenes, Salmonella typhimurium, and Mycobacterium bovis (bacillus Calmette-Guérin). The extent of erosion of established CD8(+) T cell memory was dependent on the virulence of the heterologous pathogen, not persistence. Furthermore, when antibiotics were used to comprehensively eliminate the heterologous pathogen, the numbers of memory CD8(+) T cells were not restored, indicating that erosion of preexisting memory CD8(+) T cells was irreversible. Irrespective of the initial numbers of memory CD8(+) T cells, challenge with the heterologous pathogen resulted in a similar extent of erosion of memory CD8(+) T cells, suggesting that cellular competition was not responsible for erosion. After challenge with the heterologous pathogen, effector memory CD8(+) T cells were rapidly eliminated. More importantly, erosion of preexisting memory CD8(+) T cells was abrogated in the absence of IFN-gamma. These studies help reveal the paradoxical role of IFN-gamma. Although IFN-gamma promotes the control of intracellular bacterial replication during primary infection, this comes at the expense of erosion of preexisting memory CD8(+) T cells in the wake of infection with heterologous pathogens.