We reviewed lignan physiology and lignan intervention and epidemiological studies to determine if they decreased the risks of cardiovascular disease in Western populations. Five intervention studies using flaxseed lignan supplements indicated beneficial associations with C-reactive protein and a meta-analysis, which included these studies, also suggested a lowering effect on plasma total and low-density lipoprotein cholesterol. Three intervention studies using sesamin supplements indicated possible lipid and blood pressure lowering associations. Eleven human observational epidemiological studies examined dietary intakes of lignans in relation to cardiovascular disease risk. Five showed decreased risk with either increasing dietary intakes of lignans or increased levels of serum enterolactone (an enterolignan used as a biomarker of lignan intake), five studies were of borderline significance, and one was null. The associations between lignans and decreased risk of cardiovascular disease are promising, but are yet not well established, perhaps due to low lignan intakes in habitual Western diets. At the higher doses used in intervention studies, associations were more evident.