This study investigates the role of beta-adrenergic receptors in the immunomodulatory effects of a conditioned aversive stimulus (CS). A CS is an environmental event that is not inherently aversive, but acquires aversive properties through pairings with a stimulus such as electric shock. This study evaluated the effects of administration of the beta 1-receptor selective antagonist atenolol, and the beta 2-receptor antagonist ICI 118,551 on conditioned immune alterations. Administration of either antagonist prior to presentation of the CS resulted in a dose-dependent attenuation of the CS-induced suppression of splenic T-cell proliferative response to concanavalin A, phytohemagglutinin, and the combination of ionomycin/phorbol-myristate-acetate. Furthermore, both antagonists dose-dependently attenuated the CS-induced suppression of gamma-interferon production by concanavalin-A (ConA)-stimulated splenocytes. In contrast, neither antagonist significantly attenuated the CS-induced suppression of the B-cell mitogenic response to LPS, interleukin-2 production, natural killer cell activity, or mitogenic responsiveness of blood lymphocytes. Thus it is likely that multiple mechanisms are involved in CS-induced immune alterations and these results clearly implicate beta 1 and beta 2-adrenergic receptors in a subset of immunomodulatory effects.