Human CD38 is a surface glycoprotein expressed by different immuno-competent cells such as immature and activated lymphocytes, plasma cells and natural killer cells. It has recently been reported that the CD38 molecule exerts adenosine diphosphate ribosyl cyclase activity and is associated with distinct transmembrane signaling molecules. This study reports that ligation of CD38 by specific monoclonal antibodies (mAb) induces multiple cytokine mRNA expression in cultured peripheral blood mononuclear cells (PBMC). The mRNA for tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-12 were always detected, whereas interferon-gamma and IL-10 mRNA expression were seen in most, but not all PBMC cultures. Low levels of IL-2, IL-4 and IL-5 mRNA were also found. The key observation of this work is that CD38 ligation in PBMC induces a large spectrum of cytokines, many of which overlap with those induced via CD3 activation. The main differences between CD38 and CD3 activation are the low to undetectable levels of IL-2 mRNA, and the sustained IL-1 beta and IL-6 mRNA accumulation found in PBMC cultures following treatment with anti-CD38 mAb. Furthermore, PBMC proliferation was not found to be a prerequisite for CD38-mediated cytokine induction. Together, these results suggest that human CD38 activates a signaling pathway which leads to the induction of a discrete array of cytokines, and that this pathway only partially overlaps with that controlled by T cell receptor CD3.