We examined the role of CRF, a key mediator of the endocrine response to stress, in modulating immunosuppression during the subacute stress of intermittent electrical shock over 1 h. Administration of shock to intact rats resulted in a 74% decrement in T-lymphocyte proliferation and a 59% decrease in natural killer cytotoxicity. Similar suppression of these two parameters of immune function in response to shock was noted in adrenalectomized rats as well. The immunosuppressive effects of this shock were significantly and comparably blunted when both intact and adrenalectomized animals were pretreated 1) iv with either a highly potent polyclonal CRF antibody or a specific CRF antagonist or 2) intracerebroventricularly with either a high affinity monoclonal antibody to CRF or a specific CRF antagonist. An immunomodulatory role for CRF is further supported by the findings that administration of exogenous CRF, either iv (10 micrograms/animal) or intracerebroventricularly (1 microgram/animal), resulted in significant decrements in lymphocyte proliferation and natural killer cytotoxicity, similar to those seen with the stress paradigm. Our observations indicate that CRF plays a significant role in modulating the immune response to subacute stress, largely by adrenal-independent mechanisms.