We have previously demonstrated in a murine model system that psychological stress, applied in the form of physical restraint, suppresses both the activation of splenic-derived, herpes simplex virus (HSV)-specific memory cytotoxic T-lymphocytes (CTLm) to the lytic phenotype and the production of cytokines associated with CTL activation and function. In the studies described herein, we investigated the hypothesis that an adrenal-dependent event is responsible, either in whole or in part, for these observations. While adrenalectomy was shown to abrogate stress-induced suppression of both HSV-specific CTLm activation and the production of IL-6 and IFN-gamma, the reduction in splenic cellularity associated with restraint stress remained, In addition, a role for adrenal function in the regulation of splenic cellularity and IFN-gamma production in non-stressed mice was observed. Together, these results indicate that both adrenal-dependent and adrenal-independent events, operative under both baseline and stress conditions, mediate control of the memory component of the cellular immune response to HSV infection. Overall, these studies provide insight into the mechanisms by which psychological stress modulates immune responsiveness to viral pathogens.