Human CD38, a surface glycoprotein expressed by different immunocompetent cells, is associated with distinct transmembrane signaling molecules and plays a key role in the synthesis of cyclic ADP-ribose, a calcium-mobilizing compound. This study reports that CD38 ligation by specific monoclonal antibodies (mAb) in purified peripheral blood T cells is followed by secretion of discrete cytokines. IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-gamma, and IL-10 mRNA expression were constant findings. Low levels of IL-2 mRNA were also detected in CD38-activated T lymphocyte cultures of all subjects studied. Low levels of IL-4 and IL-5 mRNA were detected in the majority of CD38-activated T cultures. Moreover, CD38 mediated cytokine induction does not require T cell proliferation or the addition of antigen presenting cells. In conclusion, human CD38 runs an activation pathway in purified T cells which operates through the induction of a cytokine profile shared by Th1 or Th2 cells.