The supplementation of corticotropin-releasing factor (CRF) into the cultures of human blood lymphocytes caused increased proliferation both in the absence and presence of T cell mitogens such as concanavalin A and phytohemagglutinin. The stimulation of concanavalin A response was much higher with CRF ligand as compared to Tyr-CRF, CRF-antagonist and sauvagine, and this response was blocked by CRF-antagonist. The lymphocyte proliferative response to stimulation by pokeweed mitogen or monoclonal antibody to CD3 antigen (OKT3) and the activity of natural killer (NK) cells was not affected by CRF. However, this neuroendocrine hormone, in addition to its ability to stimulate lymphocyte proliferation, enhanced expression of interleukin-2 receptors (IL-2R) on T cells (activated T cells) as revealed by a 2-fold increase in the proportion of IL-2R+T cells after the culture of lymphocytes for 3-5 days in the presence of CRF. Based on these findings, we suggest that CRF plays an important role in the modulation of the neuroendocrine-immune circuity.