OBJECTIVE: Sympathetic activation contributes both to the initiation and progression of heart failure. The role of chronic renal failure (CRF) in determining sympathetic overactivity in chronic heart failure (CHF) patients is unknown. We tested the hypothesis that in CHF patients, CRF could lead to increase sympathetic activity through tonic activation of excitatory chemoreceptor afferents. METHODS: We conducted a double-blind, randomized, vehicle-controlled study to examine the effect of chemoreflex deactivation on muscle sympathetic nerve activity in CHF patients with or without CRF. We compared effect of breathing 100% oxygen for 15 min in 15 stable CHF patients with CRF and 15 control CHF patients matched for age, sex, blood pressure and BMI. RESULTS: The baseline muscle sympathetic nerve activity was significantly elevated in CHF patients with CRF as compared with simple CHF patients (61 +/- 3 versus 42 +/- 4 bursts/min; P < 0.01). Administration of 100% oxygen led to a significant decrease in muscle sympathetic nerve activity in CHF patients with CRF (from 61 +/- 3 to 55 +/- 4 bursts/min; P < 0.05). By contrast, neither 100% oxygen nor room air changed muscle sympathetic nerve activity or hemodynamics in patients with solely CHF. CONCLUSION: Tonic activation of excitatory chemoreflex afferents contributes to increased efferent sympathetic activity to muscle circulation and to blood pressure control in CHF patients with CRF. These findings may have important implications for understanding how CRF contributes to the progression of CHF and increases morbidity and mortality in CHF patients.