Chronic heart failure (CHF) reduces baroreflex sensitivity. Low baroreflex sensitivity, a risk factor for sudden death, could arise partly from CHF-dependent endothelial dysfunction. Vitamin C at high doses has a protective role against CHF-related endothelial damage. This study was conducted to investigate the effect of vitamin C on baroreflex sensitivity in CHF. A study group of 33 subjects with CHF secondary to postischemic dilated cardiomyopathy with an ejection fraction </=35% and a control group (11 subjects) underwent assessment of baroreflex sensitivity by the phenylephrine method and an autonomic nervous system study by power spectral analysis. Variables were assessed after infusion of placebo and high doses of vitamin C (2.5 mg). In subjects with CHF, baroreflex sensitivity was significantly higher after vitamin C than after placebo infusion (placebo: 4.1+/-0.4 versus vitamin C: 5.3+/-0.5 ms/mm Hg, P<0.001). Low-frequency of R-R (LFRR), expressed in normalized units (NU) (P<0.05); LF/high-frequency (HF) ratio (P<0.05), and LF of SBP (LFSBP) decreased significantly; HF power (P<0.05), and alpha-HF (P<0.001) increased. Conversely, in the control group, baroreflex sensitivity and other spectral variables measured at baseline, after placebo, and after vitamin C infusion remained statistically unchanged (placebo: 10.2+/-0.1 versus vitamin C: 10.0+/-0.2 ms/mm Hg, NS). Acute administration of vitamin C at high doses improves baroreflex sensitivity and vagal sinus modulation in patients with CHF. This finding could have notable clinical and therapeutic implications. Key issues to understand are whether the beneficial effect persists during chronic administration and whether it helps to improve survival.