Beta-adrenergic blockade was used to determine if the exercise training-induced adaptations of immune response to viral infection were mediated by catecholamines in young and old mice. Young (2 month) and older (16 month) male BALB/c mice were randomly assigned to an exercise or control group and half of the mice in each group received the beta-adrenergic receptor antagonist, nadolol. After 8 weeks of moderate exercise training, mice were challenged with herpes simplex virus (HSV) 24 hours post-exercise. The results showed that exercise treatment increased anti-HSV IgM antibody, enhanced IL-10 and altered the kinetics of IFN- and IL-2 production in young and old mice. Unique to older mice, exercise decreased mitogen-induced proliferation, increased splenocytes, and tended to decrease memory cells (CD44^hi+). In contrast, exercise increased mitogen-induced proliferation, but decreased the number of splenic lymphocyte and CD4+ cells in young mice. Beta-adrenergic blockade blunted the exercise-induced changes in anti-HSV IgM, IL-2, IFN, and mitogen-induced proliferation in old, but not young mice. The findings suggest that some of the immunomodulatory effects of chronic exercise are mediated via beta-adrenergic receptors and the role of beta-adrenergic receptors is age-dependent.