Occupational exposure to lead (Pb) continues to be a serious public health concern and may pose an elevated risk of genetic oxidative damage. In Brazil, car battery manufacturing and recycling factories represent a great source of Pb contamination, and there are no guidelines on how to properly protect workers from exposure or to dispose the process wastes. Previous studies have shown that Pb body burden is associated with genetic polymorphisms, which consequently may influence the toxicity of the metal. The aim of this study was to assess the impact of Pb exposure on DNA oxidative damage, as well as the modulation of hemochromatosis (HFE) polymorphisms on Pb body burden, and the toxicity of Pb, through the analysis of 8-hydroxy-2'-deoxyguanosine (8-OHdG), in subjects occupationally exposed to the metal. Male Pb-exposed workers (n = 236) from car battery manufacturing and recycling factories in Brazil participated in the study. Blood and plasma lead levels (BLL and PLL, respectively) were determined by ICP-MS and urinary 8-OHdG levels were measured by LC-MS/MS, and genotyping of HFE SNPs (rs1799945, C → G; and 1800562, G → A) was performed by TaqMan assays. Our data showed that carriers of at least one variant allele for HFE rs1799945 (CG + GG) tended to have higher PLL than those with the non-variant genotype (β = 0.34; p = 0.043); further, PLL was significantly correlated with the levels of urinary 8-OHdG (β = 0.19; p = 0.0060), while workers that carry the variant genotype for HFE rs1800562 (A-allele) showed a prominent increase in 8-OHdG, as a function of PLL (β = 0.78; p = 0.046). Taken together, our data suggest that HFE polymorphisms may modulate the Pb body burden and, consequently, the oxidative DNA damage induced by the metal.