Physical or psychological stress can modulate immune responses in normal subjects. The effects of stress on immunity in immunocompromised hosts, however, have not been extensively investigated. Here we assess relationships among footshock stress (FS), infection with herpes simplex virus-1 (HSV-1), and immunosuppression by cyclophosphamide (CY) during the active immune response to virus in BALB/c mice. Without FS, CY significantly decreased survival and body weight gain, splenic leukocyte numbers, in vivo serum cytokine level and in vitro splenocyte cytokine production during HSV-1 infection. FS alone also significantly inhibited cell mediated anti-viral responses to HSV-1. However, FS in combination with certain CY doses led to a further significant decrease in host responses compared to either CY or FS treatment alone, including decreased survival rate, increased weight loss, lowered leukocyte numbers, reduced cytokine production in vivo and in vitro, and decreased numbers of cytokine-producing cells (IL-12 and IFNgamma). In contrast, CY, but not FS, significantly reduced in vivo anti-HSV-1 antibody secretion. These data support the hypothesis that stress can further reduce host immune responses in immunocompromised individuals. Thus, stress levels of patients should be taken into consideration prior to clinical treatment with immunosuppressants.