Abstract There is increasing evidence that neuropeptide modulation of the immune response is an important physiological phenomenon which involves the interaction of peptidergic neuromodulators with specific neuropeptide receptors on the plasma membrane of immune effector cells. Many studies have examined the effect of neuropeptides on mitogen-induced lymphocyte proliferation and immunoglobulin synthesis but very little is known about specific lymphokine production. In this study, we describe the effect of somatostatin (SOM) and vasoactive intestinal peptide (VIP) on interferon gamma (IFN-γ) production by normal human peripheral blood mononuclear cells (PBMC) stimulated in vitro with polyclonal T cell activator staphylococcal enterotoxin A (SEA). Our findings provide experimental evidence that both SOM and VIP reduce the IFN-γ production by SEA-stimulated PBMC. This reduction was time- (with maximal effect at 72h) and dose-dependent (at doses as low as 10 -11 M with maximal effect at concentrations between 10 -9 and 10 -8 M of neuropeptides). This effect was absent in resting PBMC. The meaning of inhibitory effect of VIP and SOM on IFNγ production and its role in immune response in vivo are discussed.