Overactivation of renal sympathetic nervous system and low-grade systemic inflammation are common features of hypertension. Renal denervation (RDN) reduces sympathetic activity in patients with resistant hypertension. However, its effect on systemic inflammation has not been examined. We prospectively investigated the effect of RDN on monocyte activation and inflammation in patients with uncontrolled hypertension scheduled for RDN. Ambulatory blood pressure, monocyte, and monocyte subset activation and inflammatory markers were assessed at baseline, 3 months, and 6 months after procedure in 42 patients. RDN significantly lowered blood pressure at 3 months (150.5±11.2/81.0±11.2 mm Hg to 144.7±11.8/77.9±11.0 mm Hg), which was sustained at 6 months (144.7±13.8/78.6±11.0 mm Hg). Activation status of monocytes significantly decreased at 3 months ( P <0.01) and 6 months ( P <0.01) after the procedure. In particular, classical monocyte activation was reduced at 6 months ( P <0.05). Similarly, we observed a reduction of several inflammatory markers, including monocyte–platelet aggregates (3 months, P <0.01), plasma monocyte chemoattractant protein-1 levels (3 months, P <0.0001; 6 months, P <0.05), interleukin-1β (3 months, P <0.05; 6 months, P <0.05), tumor necrosis factor-α (3 months, P <0.01; 6 months, P <0.05), and interleukin-12 (3 months, P <0.01; 6 months, P <0.05). A positive correlation was observed between muscle sympathetic nerve activity and monocyte activation before and after the procedure. These results indicate that inhibition of sympathetic activity via RDN is associated with a reduction of monocyte activation and other inflammatory markers in hypertensive patients. These findings point to a direct interaction between the inflammatory and sympathetic nervous system, which is of central relevance for the understanding of beneficial cardiovascular effects of RDN.