Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that leads to increased risk of cardiovascular disease. This study was conducted to evaluate the effects of a Mindfulness-Based Stress Reduction (MBSR) programme on SNS activity in CKD patients. Participants with CKD stages III-IV were randomized to the 8 week MBSR programme or Health Enhancement Program (HEP; a structurally parallel, active control group). Intraneural measures of SNS activity directed to muscle [muscle sympathetic nerve activity (MSNA)] via microneurography was recorded at rest and during stress manoeuvres (mental arithmetic, handgrip exercise and cold pressor test). Data analyses were performed based on the intent-to-treat principle. In total, 29 participants (64 ± 9 years; 86% males) completed the intervention with 17 in the MBSR and 12 in the HEP groups. There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post-intervention) interaction in MSNA reactivity to mental stress (P = 0.029), with a significant reduction in the mean ∆MSNA over 3 min of mental arithmetic at post-intervention (10.3 ± 4.2-5.9 ± 5.6 bursts/min, P < 0.001; Hedges' g = -0.858, 95% confidence interval [-1.578, -0.167]), while no change was observed within the HEP group (P = 0.818). Reduced ∆MSNA during handgrip exercise was also observed, while ∆MSNA during the cold pressor test and resting MSNA remained unchanged in both groups from baseline to post-intervention. In this randomized controlled trial, patients with CKD had a reduction of sympathetic reactivity during mental stress and static handgrip exercise following 8 weeks of MBSR but not after HEP. Our findings demonstrate that mindfulness training is feasible and may have clinically beneficial effects on autonomic function in CKD. KEY POINTS: Question: Does the Mindfulness-Based Stress Reduction (MBSR) programme reduce sympathetic activity in patients with chronic kidney disease (CKD)? Finding: In this randomized controlled trial including 29 patients with CKD, 8 weeks of MBSR decreased sympathetic reactivity to mental stress compared to the control Health Enhancement Program (HEP). Meaning: These finding suggest that mindfulness training may have clinically beneficial effects on autonomic function in CKD.