Key points It is believed that the CNS controls inflammation via the autonomic nervous system, but the strength of this action and the neural pathways responsible are unclear. In anaesthetized rats we measured the inflammatory response to lipopolysaccharide (LPS, 60 μg kg−1, i.v.) by plasma tumour necrosis factor α (TNFα) levels 90 min later. Bilateral section of the splanchnic sympathetic nerves before LPS treatment resulted in a 5‐fold increase in the plasma TNFα response, but bilateral vagotomy had no effect. LPS treatment strongly increased efferent activity in the splanchnic sympathetic nerve and its splenic branch; vagotomy did not affect this. These results show that, besides directly stimulating inflammation, LPS engages a powerful anti‐inflammatory reflex that can inhibit the plasma TNFα response by 80%. The reflex efferent arm is in the splanchnic sympathetic nerves; the vagi play no part. Abstract We investigated a neural reflex that controls the strength of inflammatory responses to immune challenge – the inflammatory reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg−1), we found strong increases in plasma levels of the key inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5‐fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural reflex that is powerful enough to cause an 80% suppression of the acute systemic inflammatory response. The efferent arm of this reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this reflex could play an important role in immune function as well as inflammatory diseases.