Dietary sodium is associated with changes in vascular volume and reactivity, possibly mediated by alterations in eNOS activity. Caveolin-1 (Cav-1) binds eNOS and limits its translocation and activation. To test the hypothesis that Cav-1 participates in dietary sodium-mediated effects on vascular function, we assessed vascular responses and nitric oxide (NO)-mediated mechanisms of vasorelaxation in Cav-1 knockout (KO) and wild type mice (WT) placed on high salt (HS, 4% NaCl) or low salt (LS, 0.08% NaCl) diet for 16 days. BP was elevated in L-NAME treated HS mice and more so in KOs than WTs, and was reduced during LS diet. Phenylephrine caused vascular contraction that was reduced in KO (0.25±0.06) vs. WT (0.75±0.22) on a HS but not on a LS diet. Acetylcholine caused aortic relaxation in WT mice on HS (23.6±3.5%) and LS (23.7±5.5%), stronger in KO HS (72.6±6.1%) and more so in KO LS mice (93.6±3.5%). Aortic and cardiac eNOS mRNA expression, as well as cardiac eNOS protein (total and phosphorylated) was increased in KO vs. WT mice on HS diet, and the genotypic differences were less apparent during LS diet. Thus, Cav-1 deficiency during HS diet is associated with decreased vasoconstriction, increased vasorelaxation, and increased eNOS expression/activity, and these effects are altered during LS diet. The data suggest that endothelial Cav-1, likely via eNOS activity modulation, plays a prominent role in vascular function regulation during substantial changes in dietary sodium intake.