Chronic exposure to arsenic is associated with increased morbidity and mortality from cardiovascular disease (CVD); however, plausible biomarker for early prediction and the underlying mechanism of arsenic-related CVD have not yet been clearly understood. Endothelial dysfunction plays a central role in the development of CVD. We hypothesized that endothelial damage or dysfunction is an important aspect and may be an early event of arsenic-related CVD. Soluble thrombomodulin (sTM) in serum is thought to be a specific and stable marker for endothelial damage or dysfunction. This study was designed to evaluate the association between chronic exposure to arsenic and sTM among human subjects in arsenic-endemic and non-endemic rural areas in Bangladesh. A total of 321 study subjects (217 from arsenic-endemic areas and 104 from a non-endemic area) were recruited. Subjects' arsenic exposure levels (i.e., drinking water, hair and nail arsenic concentrations) were measured by Inductively Coupled Plasma Mass Spectroscopy. The subjects' serum sTM levels were quantified by immunoassay kit. The average sTM levels of the subjects in arsenic-endemic and non-endemic areas were 4.58 ± 2.20 and 2.84 ± 1.29 (ng mL-1) respectively, and the difference was significant (p<0.001). Arsenic exposure levels showed a significant (water arsenic: rs = 0.339, p<0.001, hair arsenic: rs = 0.352, p<0.001 and nail arsenic: rs = 0.308, p<0.001) positive associations with sTM levels. Soluble TM levels were higher in the higher exposure gradients if we stratified the subjects into tertile groups (low, medium and high) based on the arsenic concentrations of the subjects' drinking water, hair and nails. Finally, increased levels of sTM were negatively correlated with high density lipoprotein cholesterol (HDL-C), and positively correlated with intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Results of this study show that chronic exposure to arsenic has mild to moderate association with sTM levels.