To understand whether human paraoxonase 1 (PON1) would modulate the risk for arsenic-related atherosclerosis, we studied 196 residents from an arseniasis-endemic area in Southwestern Taiwan and 291 age- and sex-matched residents from a nearby control area where arsenic exposure was found low. Carotid atherosclerosis was defined by a carotid artery intima-media wall thickness (IMT) of >1.0 mm. Prevalence of carotid atherosclerosis was increased in the arseniasis-endemic area as compared to the control area after adjustment for conventional risk factors (OR=2.20, p<0.01). The prevalence was positively associated with cumulative arsenic exposure (mg/L-year) in a dose-dependent manner. Multiple logistic regression analysis showed that in the endemic group, low serum PON1 activity was an independent risk factor for atherosclerosis (OR=4.18 low vs. high, p<0.05). For those of low PON1 activity and high cumulative arsenic exposure, the odds ratio for the prevalence of atherosclerosis was further increased up to 5.68 (p<0.05). No significant association was found between atherosclerosis and four polymorphisms of the PON gene cluster (PON1 -108C/T, PON1 Q192R, PON2 A148G, PON2 C311S). However, genetic frequencies of certain alleles including PON1 Q192, PON2 G148 and PON2 C311 were found increased in the endemic group as compared to the controls and a general Chinese population, indicating a possible survival selection in the endemic group after a long arsenic exposure history. Our results showed a significant joint effect between arsenic exposure and serum PON1 activity on carotid atherosclerosis, suggesting that subjects of low PON1 activity may be more susceptible to arsenic-related cardiovascular disease.