A large body of evidence indicates that metazoan innate immunity is regulated by the nervous system, but the mechanisms involved in the process and the biological importance of such control remain unclear. We show that a neural circuit involving npr-1 , which encodes a G protein–coupled receptor (GPCR) related to mammalian neuropeptide Y receptors, functions to suppress innate immune responses. The immune inhibitory function requires a guanosine 3′,5′-monophosphate–gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we show that npr-1 – and gcy-35 –expressing sensory neurons actively suppress immune responses of nonneuronal tissues. A full-genome microarray analysis on animals with altered neural function due to mutation in npr-1 shows an enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/p38 mitogen-activated protein kinase signaling pathway. These results present evidence that neurons directly control innate immunity in C. elegans , suggesting that GPCRs may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate immune responses.