A murine model of herpes simplex virus (HSV) infection was used to examine the role of the adrenal gland in restraint stress-induced suppression of viral immunity. Adrenal-dependent mechanisms were important for suppressing the generation of HSV-specific cytotoxic T lymphocytes (CTL) but not the associated diminished lymphadenopathy in response to local HSV infection. While exogenous corticosterone administration alone was unable to suppress lymphadenopathy and CTL generation in adrenalectomized mice, an adrenal-independent mechanism induced by restraint stress functioned in synergy with corticosterone to suppress lymphadenopathy and CTL development. These results suggest that both adrenal-dependent and independent mechanisms contribute to stress-induced modulation of HSV immunity.