This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg, iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 hour after the injection. Blockade of TRPV1 with its selective antagonist, capsazepine (CAPZ, 3 mg/kg, iv), impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 hour after CAPZ plus LPS injections compared to LPS injection alone (45 ± 5 vs. 25 ± 4 mmHg, P < 0.05). Blockade of the neurokinin-1 (NK1) receptor with its selective antagonists, RP67580 (5 mg/kg, iv) or L-733,060 (4 mg/kg, iv), prevented recovery considering that falls in MAP were not different 1 hour after injections of NK1 antagonists plus LPS from their peak decreases (66 ± 9 vs. 74 ± 5 mmHg, or 60 ± 7 vs. 69 ± 3 mmHg, respectively, P>0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (EPI) levels compared to vehicles, and the increases in plasma SP, NE, and EPI were significantly inhibited by CAPZ or RP67580, respectively. The survival rate at 24 or 48 hours after LPS injection (20 mg/kg, ip) was lower in conscious rats pretreated with CAPZ or RP67580 compared to rats treated with LPS alone (P<0.05). Thus, our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition.