Metal exposure is associated with increased oxidative stress (OS), which is considered an underlying mechanism of metal-induced toxicity. Malondialdehyde (MDA) is a final product of lipid peroxidation, and it has been extensively used to evaluate metal-induced OS. Pro-oxidant effects produced by metals can be mitigated by paraoxonase 1 (PON1), an antioxidant enzyme known to prevent cardiovascular disease and atherosclerosis. Among other factors, the Q192R polymorphism and the exposure to heavy metals have been known to alter PON1 activity. Here, we evaluated the association of blood lead (Pb), cadmium (Cd) and mercury (Hg) levels with PON1 activity, and with MDA concentrations in a randomly selected sample of Brazilian adults aged 40 years or older, living in an urban area in Southern Brazil. A total of 889 subjects were evaluated for blood Pb and Cd levels, and 832 were tested for Hg. Geometric mean of blood Pb, Cd and Hg was 1.93 μg/dL, 0.06 μg/L and 1.40 μg/L, respectively. PON1 activity was significantly different among various genotypes: QQ (PON1=121.4 U/mL), QR (PON1=87.5 U/mL), and RR (PON1=55.2 U/mL), p<0.001. PON1 genotypes were associated only with Cd blood levels. Those with QR genotype had Cd concentrations higher (0.07 μg/L) than those with the RR genotype (0.04 μg/L) with p=0.034. However, PON1 activity was not significantly associated with metal concentrations. Cluster analysis showed that men who reported to be current smokers and drinkers with higher blood Pb and Cd levels, had significantly lower PON1 activity than non-smokers or -drinkers, and women with lower Pb and Cd levels. RR genotype carriers had lower PON1 activity than those with the QR genotype, and had higher levels of Pb and Cd compared with other genotype carriers. For blood Hg, no association with PON1 activity or genotype was noted. We found low levels of Pb, Cd and Hg in environmentally exposed Brazilian adults. Cd concentrations were increased in subjects with QR genotype. Those with RR genotype had lower PON1 activity and higher levels of Pb and Cd than other genotype carriers. The results of cluster analysis suggested that smoking status exerts a significant influence on PON1 activity. Other studies with environmentally exposed populations are required to further clarify whether low blood levels of metals influence OS biomarkers.