Objective: To examine the regulation of interferon (IFN)-γ release by cells derived from submaxillary lymph nodes of rats subjected to an acute or chronic superior cervical ganglionectomy (SCGx). Methods: A unilateral SCGx and a contralateral sham operation were performed. Twenty hours or 7 days later cells from submaxillary lymph nodes were incubated for 24 h without any additional treatment (experiment 1), after adding lipopolysaccharide or concanavalin A (experiment 2) or after adding norepinephrine (NE, 10–8M; experiment 3). IFN-γ concentration in the culture media was measured by ELISA. Results: Compared to controls, cells obtained from lymph nodes at a time of degeneration of sympathetic nerve terminals released more IFN-γ, whereas those derived from chronically SCGx lymph nodes released less IFN-γ. Stimulation of IFN-γ release by mitogens was detectable in the innervated or acutely denervated lymph nodes, but not in chronically denervated lymph nodes. When the effect of 10–8M NE on IFN-γ release was tested, the neurotransmitter augmented cytokine release in cells prepared from chronically denervated lymph nodes only. Conclusion: The microenvironment provided by local sympathetic nerves is essential to enable an appropriate IFN-γ release by submaxillary lymph node cells to occur.