Antioxidants reduce arterial stiffness, but the effects previously reported are weak. A systematic review of the antioxidants vitamin E, vitamin C, vitamin A, and beta-carotenes (the most commonly studied antioxidants) on pulse wave velocity (PWV) found an effect size of only −0.20 (approximately −16 m/s or −2.5%). Studies in rats of the potent pro-oxidant substance acetaldehyde have shown that combinations of sulfur-containing antioxidants, including thiamine and l-cysteine, with ascorbic acid potently protect against oxidative-stress-mediated mortality. The effects of these combinations of oxidants on PWV have not been studied. The present study evaluated the effects of 2 weeks of therapy with a combination of sulfur-containing antioxidants (cysteine, thiamine, and pyridoxine) in combination with ascorbic acid on stiffness index (SI), a measure of arterial stiffness that is strongly correlated with PWV, using a Pulse Trace recorder in a diverse group of 78 volunteers. SI fell by −1.7 m/s relative to placebo (95% confidence intervals −0.6 to −2.7 m/s), a reduction of −19% (95% confidence intervals −9% to −31%). The Glass effect size was 1.4, indicating a very strong treatment effect which was substantially greater than the effect size found in previous studies of antioxidants. PWV reduction was correlated significantly with increasing age. Further studies of similar antioxidant combinations are required to determine whether they are of value in the treatment or prevention of cardiovascular disease.