Using a murine model, we have previously shown that restraint stress is able to suppress the development of herpes simplex virus (HSV)-specific cytotoxic T lymphocytes (CTL) and natural killer (NK) cell activity in the popliteal lymph nodes following local footpad infection. These studies of the primary cell-mediated immune response to HSV infection have been extended to examine the effects of a similar stressor on the development of HSV-specific memory CTL (CTLm) following local and systemic HSV infection. In addition, the effect of stress on HSV-specific CTLm localization and proliferation in the popliteal lymph node following reexposure to HSV was investigated. Lastly, the ability to stimulate HSV-specific CTLm to the lytic phenotype under conditions of restraint stress was examined. Restraint stress did not inhibit the generation of HSV-specific CTLm. However, restraint stress inhibited the ability to activate CTLm to the lytic phenotype. In HSV seropositive mice (primed prior to stress), restraint stress prevented the in vivo activation and/or migration of HSV-specific CTLm in the popliteal lymph nodes. These findings demonstrate that activation of HSV-specific immunological memory can be inhibited by physiological changes associated with stress. Such immune inhibition may provide a possible mechanism for the development of recrudescent herpetic disease.