Western diet (WD) intake increases morbidity of obesity, diabetes, and salt sensitive hypertension albeit mechanisms are largely unknown. We tested the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channels are activated during WD intake to protect against salt-induced increases in blood pressure possibly via enhancing natriuresis. Wild-type (WT, C57BL/6) or gene-targeted TRPV1-null mutant (TRPV1-/-) mice were fed a normal (CON) or Western (WD) diet for 16-18 weeks. Mean arterial pressure (MAP), determined by radiotelemetry after acute sodium loading (NS, 0.9% NaCl) or vehicle (C) by gavage with or without treatment with Nω-nitro-l-arginine methyl ester (L-NAME, 10mg/kg, ip.) or a TRPV1 agonist, N-oleoyldopamine (OLDA, 0.1mg/kg, ip), was not different between two strains fed a CON diet. WT or TRPV1-/- mice fed a WD diet had increased MAP after NS, with a greater magnitude in TRPV1-/- mice (p<0.05). OLDA decreased while L-NAME increased MAP in WT-WD-NS but not TRPV1-/-WD-NS mice (p<0.05). The urinary nitrates plus nitrites excretion (UNOx, umol*4h urine/kg BW), an indicator of renal nitric oxide (NO) production, was increased in both strains fed a CON diet after NS (p<0.05). OLDA further increased while L-NAME prevented NS-induced increases in UNOx in WT-CON-NS only or in both strains, respectively. TRPV1 ablation with WD intake decreased UNOx levels before NS and abolished NS-induced increment in UNOx (WT-WD-C: 0.3 ±0.06 vs. TRPV1-/-WD-C: 0.2 ±0.05; and WT-WD-NS: 0.7 ±0.1 vs. TRPV1-/-WD-NS: 0.3 ±0.1; p<0.05). OLDA further increased while L-NAME prevented NS-induced increment in UNOx in WT-WD-NS mice only (p<0.05). Urinary sodium excretion was increased in both strains fed a CON diet after NS (p<0.05), which was unaffected by OLDA or L-NAME. UNa was increased in WT-WD-NS but not TRPV1-/-WD-NS after NS. OLDA further increased while L-NAME prevented NS-induced increases in UNa in WT-WD-NS only. Thus, TRPV1 ablation increases salt sensitivity during WD intake possibly via impaired NS-induced renal NO production and sodium excretion. Activation of TRPV1 with OLDA enhances renal NO production and sodium excretion, resulting in prevention of increased salt sensitivity during WD intake.