Significance: Despite continuous advances in the prevention of cardiovascular disease (CVD), critical issues associated with an unhealthy lifestyle remain an increasing cause of morbidity and mortality in industrialized countries. Recent Advances: A growing body of literature supports a specific role for vitamin C in a number of reactions that are associated with vascular function and control including, for example, nitric oxide bioavailability, lipid metabolism, and vascular integrity. Critical Issues: A large body of epidemiological evidence supports a relationship between poor vitamin C status and increased risk of developing CVD, and the prevalence of deficiency continues to be around 10%–20% of the general Western population although this problem could easily and cheaply be solved by supplementation. However, large intervention studies using vitamin C have not found a beneficial effect of supplementation. This review outlines the proposed mechanism by which vitamin C deficiency worsens CVD progression. In addition, it discusses problems with the currently available literature, including the discrepancies between the large intervention studies and the experimental and epidemiological literature. Future Directions: Increased insights into vitamin C deficiency-mediated CVD progression will enable the design of future randomized controlled trials that are better suited to test the efficacy of vitamin C in disease prevention as well as the identification of high-risk individuals which could possibly benefit from supplementation. Antioxid. Redox Signal. 19, 2084–2104.
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