Regulatory interactions and neuroanatomic pathways have been described between the sympathetic nervous system and the immune system. It is not clear whether these pathways are activated during immune responses and if target specificity provides selective regulation of immune organs. The present study examined whether systemic injection of endotoxin [lipopolysaccharide (LPS)] induces sympathetic outflow to an immune organ (spleen). Sympathetic nerve activity was recorded from either the splenic or renal nerve of adult male rats after intravenous injections of LPS. Splenic nerve activity increased in a dose-dependent manner up to 175% of control after injection of LPS, with an onset time of 17.1-23.5 min. In contrast, renal nerve recordings showed a significantly slower onset time of 37.1-52.6 min at similar doses. In addition, splenic nerve recordings of 8/8 rats responded to 10 micrograms of LPS, whereas only 4/11 positive renal nerve responses were observed at this dose. The magnitude of the responses of both splenic and renal nerves were comparable. These data suggest that the splenic nerve responds to and is more sensitive to LPS-stimulated sympathetic activation in terms of latency and frequency of responses. Thus sympathetic outflow can be directed to an immune organ in response to a stimulus known to activate the immune system.