Arsenic exposure from drinking water has been linked to subclinical and clinical outcomes of cardiovascular disease (CVD). However, no large-scale studies have evaluated whether the cardiovascular effects of arsenic exposure could be modified by genetic factors. Using data from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, we evaluated whether the association between arsenic exposure and CVD risk or carotid artery Intima-Media Thickness (cIMT) differs by single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, and inflammation and endothelial dysfunction. We found significant interactions between well-water As and two SNPs in ICAM1 and VCAM1 in CVD risk, and of both well-water As and urinary As with 3 SNPs in AS3MT in cIMT. Our data provide novel evidence that the cardiovascular effects of arsenic exposure may vary with some common genetic variants in genes related to arsenic metabolism and endothelial dysfunction.