Biologic activities of IL-16 have been well described (e.g., chemotaxis of CD4+ cells, CD25 upregulation, secretion of IL-1b, IL-4 and TNF-a secretion) but very few signaling events have been described. To gain a better understanding of how the biologic activities of IL-16 are regulated following receptor engagement (CD4) we have analyzed the activation state of numerous STAT proteins in primary human peripheral blood mononuclear cells (PBMCs) and the human monocytic cell line THP-1 following IL-16 stimulation. Of the four STAT proteins tested, only STAT6 was activated (phosphorylated) in a dose-dependant manner by IL-16. The activation of STAT6 was completely abolished when IL-16 was pre-incubated with soluble CD4 (the IL-16 cell surface receptor), demonstrating the need for CD4 engagement in STAT6 activation. These results are the first to demonstrate a link between IL-16 and STAT6 activation.