Overnight treatment of murine leukocytes with corticotropin-releasing hormone (CRH) and arginine vasopressin enhances natural killer cell activity. Moreover, the opioid receptor antagonist, naloxone, as well as the delta-class opioid receptor antagonist, naltrindole, can block this effect. The responsivity of murine leukocytes to CRH is both dose- and time-dependent. The effector cells are both MAC-1 and Thy-1.2 antigen-positive. Whereas β-endorphin is also shown to enhance natural killer cell activity in a naloxone-reversible manner, adrenocorticotropic hormone (ACTH) has a negligible effect. Macrophage depletion prior to incubation with CRH blocks the CRH-induced natural killer cell augmentation. These results suggest hypothalamic-releasing hormones such as CRH may have a biologically relevant role in the modulation of immune cells either directly or indirectly through the induction of neuropeptide hormones known to have immunomodulatory capabilities. © 1990.