Abstract There is some evidence that oxidative stress plays a role in lead-induced toxicity. Mechanisms for dealing with oxidative stress may be of particular relevance in the brain given the high rate of oxygen metabolism. Using a hospital-based case-control study, we investigated the role of oxidative stress in the potential carcinogenicity of lead through examination of effect modification of the association between occupational lead exposure and brain tumors by single nucleotide polymorphisms in genes with functions related to oxidative stress. The study included 362 patients with glioma (176 of which had glioblastoma multiforme), 134 patients with meningioma, and 494 controls. Lead exposure was estimated by expert review of detailed job history data for each participant. We evaluated effect modification with 142 single nucleotide polymorphisms using likelihood ratio tests that compared nested unconditional logistic regression models that did and did not include a cross-product term for cumulative lead exposure and genotype. When the analyses were restricted to cases with glioblastoma multiforme, RAC2 rs2239774 and two highly correlated GPX1 polymorphisms (rs1050450 and rs18006688) were found to significantly modify the association with lead exposure (P ≤ 0.05) after adjustment for multiple comparisons. Furthermore, the same GPX1 polymorphisms and XDH rs7574920 were found to significantly modify the association between cumulative lead exposure and meningioma. Although the results of this study provide some evidence that lead may cause glioblastoma multiforme and meningioma through mechanisms related to oxidative damage, the results must be confirmed in other populations. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1841–8)