CVD is a major cause of mortality and morbidity in the Western world. In recent years its importance has expanded internationally and it is believed that by 2020 it will be the biggest cause of mortality in the world, emphasising the importance to prevent or minimise this increase. A beneficial role for vitamins in CVD has long been explored but the data are still inconsistent. While being supported by observational studies, randomised controlled trials have not yet supported a role for vitamins in primary or secondary prevention of CVD and have in some cases even indicated increased mortality in those with pre-existing late-stage atherosclerosis. The superiority of combination therapy over single supplementation has been suggested but this has not been confirmed in trials. Studies have indicated that beta-carotene mediates pro-oxidant effects and it has been suggested that its negative effects may diminish the beneficial effects mediated by the other vitamins in the supplementation cocktail. The trials that used a combination of vitamins that include beta-carotene have been disappointing. However, vitamin E and vitamin C have in combination shown long-term anti-atherogenic effects but their combined effect on clinical endpoints has been inconsistent. Studies also suggest that vitamins would be beneficial to individuals who are antioxidant-deficient or exposed to increased levels of oxidative stress, for example, smokers, diabetics and elderly patients, emphasising the importance of subgroup targeting. Through defining the right population group and the optimal vitamin combination we could potentially find a future role for vitamins in CVD.