The spontaneous non obese diabetic (NOD) mouse model of Sjögren's syndrome provides a valuable tool to study the onset and progression of both autoimmune response and secretory dysfunction. Vasoactive intestinal peptide (VIP) is a neuro and immunopeptide with prosecretory effect in salivary glands and anti-inflammatory actions in various models of autoimmune disease. Our purpose was to analyze the response of peritoneal macrophages to an inflammatory stimulus during the decline of salivary secretion in NOD mice and the potential anti-inflammatory effect of VIP. We present evidence of an increased nitric oxide production by peritoneal macrophages of NOD mice in basal and lipopolysaccharide (LPS)+IFN-gamma-stimulated conditions and a lower IL-10 response to LPS compared with normal BALB/c mice. VIP inhibited LPS-induced TNF-alpha, IL-12 and nitrites accumulation in NOD macrophages while it increased IL-10 production. VIP effect was prevented by an anti-IL-10 monoclonal antibody and it showed an additive effect on exogenously added IL-10 only in NOD mice. The inhibitory effect of VIP-induced IL-10 on nitrites was mediated by COX metabolites mostly in NOD cells as indomethacine inhibited both the increase in IL-10 and the reduction of nitrites exerted by VIP. We conclude that both PGE2 and VIP inhibit nitric oxide production and increase IL-10 induced by LPS in NOD macrophages and VIP effect is mediated through an increase of COX metabolites and IL-10.