Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt-sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ET_B receptors (ET_B-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt-sensitivity in ET_B-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal (0.49% NaCl) and high (4.0% NaCl) salt diets. Denervation reduced mean arterial pressure in ET_B-def rats compared to sham-operated controls by 12 ± 3 mmHg; however, denervation did not affect the increase in blood pressure following two weeks of high salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic to parasympathetic tone (LF/HF) during normal salt diet and vasomotor LF/HF tone during high salt diet in ET_B-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ET_B-def rats.