Lead exposure is a well known cause of cardiovascular damage, including atherosclerosis. Paraoxonase 1 (PON1), a high-density lipoprotein-associated antioxidant enzyme, is capable of hydrolyzing oxidized lipids and thus it protects against atherosclerosis. The mechanism by which heavy metals inhibit serum PON1 activity is still not clear. Our aim was to detect the association between lead exposure and serum PON1 activity and lipid profile and also to study the polymorphism of the PON1 gene.A case-control, cross-sectional study conducted from June 2008 until May 2009.Male workers (n=100) in a lead battery manufactory were recruited for this study. They were compared with 100 male age-matched workers not exposed to lead (control group). Serum lipid profile, paraoxonase activity and lead were measured in blood samples. The DNA was extracted for detecting the Q192R polymorphism of the PON1 gene by polymerase chain reaction followed by restriction fragment length polymorphism.There was significant difference in triglycerides, total cholesterol and high-density lipoprotein cholesterol (HDL-C) (P=.01, .05 and .04, respectively) between cases and controls. Multiple linear regression analysis showed that blood lead levels were significantly associated with decreased serum paraoxonase activity (P=.03) in lead workers. The paraoxonase genotype QR was the most prevalent in 34/53 subjects (64%) among the lead-exposed groups, while the genotype QQ was more prevalent in the control group, in 15/25 subjects (60%), with a significant difference between the control and other groups (P<.05).Lead exposure is associated with increased triglycerides, total cholesterol and low-density lipoprotein cholesterol and decreased HDL-C. Because of the protective role of PON1 in the development of atherosclerosis, a decrease in serum PON1 activity due to lead exposure may render individuals more susceptible to atherosclerosis.