Transient potential vanilloid 1 (TRPV1) receptor is an ion channel receptor primarily localized on sensory nerves and activated by specific stimuli to initiate and amplify pain and inflammation, as typified by murine models of scald and arthritis. Little is known of the role of TRPV1 in sepsis, an infective disease associated with inflammation. Through use of a suble‐thal murine model of lipopolysaccharide‐induced peritoneal sepsis, we provide novel evidence that genetic deletion of TRPV1 leads to an enhanced onset of various pathological components of systemic endotox‐emia. Paired studies of TRPV1 knockout (KO) and wild‐type mice demonstrate significantly enhanced hypotension (56±2% vs. 38±6% decrease in blood pressure, n=12), hypothermia (13±3% vs. 7±1% decrease in core temperature, n=6), and peritoneal exudate mediator levels (TNF‐α, 0.78±0.2 vs. 0.38±0.1 ng/ml; nitrite, for NO, 35±10 vs. 15±3 μM; n=8) in TRPV1 KO mice, indicating loss of protective effect. Findings correlated with liver edema and raised plasma levels of aspartate aminotransferase in TRPV1 KO mice. These data suggest that TRPV1 may play an important regulatory role in sepsis independent of the major sensory neuropeptide substance P. The findings are relevant to developing strategies that increase the beneficial, and reduce the harmful, components of sepsis to prevent and treat this often fatal condition.—Clark, N., Keeble, J., Fernandes, E. S., Starr, A., Liang, L., Sugden, D., de Winter, P., Brain, S. D. The transient receptor potential vanilloid 1 (TRPV1) receptor protects against the onset of sepsis after endotoxin. FASEB J. 21, 3747–3755 (2007)