An increasing body of evidence supports the existence of a strong link between inflammation, endothelial dysfunction, and the onset and progression of atherosclerosis. However, a cause-effect relationship between these phenomena has not been demonstrated yet. Although some inflammatory markers, such as C-reactive protein, have been recently shown to improve risk stratification and to strongly predict cardiovascular outcome, it is largely unknown whether modifications of these markers might provide salutary effects and reduce cardiovascular morbidity and mortality. The B-vitamin folic acid has recently gained attention because of its potential to provide beneficial effects on surrogate end-points, such as endothelial function, in patients at high cardiovascular risk. However, the role of folic acid in mitigating the pro-inflammatory state associated with atherosclerosis is controversial. Despite the theoretical arguments supporting the potential anti-atherosclerotic and anti-inflammatory effects of folic acid, the current evidence is limited, deriving from small trials on different study populations, using folic acid often in combination with other vitamins and for different treatment periods. This review will consider the current evidence supporting the role of some well-established inflammatory markers in predicting cardiovascular outcomes, the mechanisms by which folic acid might exert anti-inflammatory effects, the epidemiological data relating folic acid concentrations with inflammatory markers, the published interventional studies on the effects of folic acid supplementation on these markers, and the factors that need to be considered in designing future trials.