Upon infection with Salmonella, a host develops an immune response to limit bacterial growth and kill and eliminate the pathogen. Salmonella has evolved mechanisms to remain dormant within the body, only to reappear (reactivate) at a later time when the immune system is abated. We have developed an in vivo model for studying reactivation of Salmonella enterica serovar Typhimurium infection in mice. Upon subcutaneous infection, C3H/HeN (Ity(r)) mice showed an increase in bacterial numbers in livers and spleens, which reached a peak on day 19. After full recovery from the infection, these mice were irradiated or depleted of CD4(+) T cells. The mice displayed a secondary infection peak in livers and spleens with a course similar to that of the primary infection. We concluded that CD4(+) T cells are involved in active suppression of S. enterica serovar Typhimurium during latency. The role of CD4(+) T cells during primary infection with S. enterica serovar Typhimurium is well established. This is the first study to describe a role of CD4(+) T cells during the latent phase of S. enterica serovar Typhimurium infection.