The effect of cold stress on immunocompetence was investigated in mice intragastrically intubated with sheep red blood cells. Cold stress was found to consistently augment total IgG and IgM production by splenic lymphocytes. In addition, antigen-specific IgM production by cultured splenic lymphocytes obtained from cold stressed animals was enhanced compared to unstressed mice. However, serum levels of total and antigen-specific immunoglobulins were suppressed or unaltered following cold stress. The α-adrenoceptor antagonist, phentolamine, could block the effects mediated by cold stress while the β-adrenoceptor antagonist, propranolol, potentiated the action of cold stress. Taken together, the data indicate cold stress-mediated enhancement in immunoglobulin production by orally immunized animals takes place through the activation of α-adrenergic pathways. The results also suggest α- and β-adrenergic pathways independently regulate antibody production following oral administration of antigen. These observations illustrate the integrative nature of the immune and neuroendocrine systems. © 1992.