Epidemiologic studies have linked arsenic exposure from drinking water to elevated risks of CardioVascular Disease (CVD). However, the underlying mechanism by which arsenic may lead to CVD is unclear. We conducted a series of cross-sectional and prospective analyses using data from the Health Effects of arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh. We found that chronic arsenic exposure from drinking water was positively associated with plasma levels of sVCAM-1 and the association was stronger in people with higher body mass index; past long-term arsenic exposure was related to subsequent QT-interval prolongation, especially in women; the proportion of monomethylarsonic acid in urine was positively associated with heart disease risk, especially among smokers. Our results indicate that mechanisms underlying arsenic exposure-related CVD may involve inflammation, endothelial dysfunction, electrocardiogram abnormalities, and incomplete arsenic methylation capacity.