Background: Environmental tobacco smoke (ETS) contains toxic and carcinogenic substances that are known to cause diseases and premature death. Microsomal epoxide hydrolase (mEH) is a key enzyme in metabolizing exogenous carcinogens such as reactive oxygen species (ROS) products of cigarette-smoking. Two functional polymorphisms in its gene (mEPHX), exon 3 (Tyr113His) and exon 4 (His139Arg) can alter the enzyme activity, suggesting their possible association with lung cancer. Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide radicals, thus protects against oxidative stress in lung tissues. One coding polymorphism (Val16Ala) in MnSOD, is known to disrupt proper enzyme function. Aim of the work: The present study aimed to evaluate the role antioxidant enzymes activity and genetic polymorphisms in modifying the susceptibility to lung cancer among individuals exposed to ETS.Subjects and Methods: This was a case-control study conducted on 150 male subjects divided into three groups: 50 lung cancer patients, 50 chronic smokers and 50 passive smokers. Genotyping of mEPHX exon 3 (Tyr113Hist) and exon 4 (Hist139Arg) polymorphisms was done by PCR-RFLP technique followed by calculation of predicted mEH enzyme activity. MnSOD (Val16Ala) polymorphism was detected by Real time PCR technique using TaqMan SNP genotyping assay. Erythrocyte MnSOD activity was measured spectrophotometrically using kinetic reactions.Results: mEPHX exon 3 polymorphism was significantly associated with increased risk of lung cancer among ETS exposed individuals (both active and passive smokers) (Tyr/Tyr vs His/His: OR: 5.5, P=0.007). A significant association was found between the carriers of the (His) allele and lung cancer risk (OR: 2.9, P<0.001). mEPHX exon 4 contributed to increased lung cancer risk among ETS exposed individuals (His/His vs Arg/Arg: OR: 2.8, P=0.036). Similarly, carriers of the (Arg) allele had an increased risk of lung cancer (OR: 2.1, P=0.024). However, the present work showed no significant association between MnSOD Val16Ala polymorphism and lung cancer (Val/Val vs Ala/Ala: OR: 1.3, P=0.43), although lung cancer and chronic smokers groups had significantly lower MnSOD enzyme activity than passive smokers group (2.3U/ml and 2.2U/ml vs 2.9U/ml, P=0.03). Moreover, there was a statistically significant negative correlation between cigarette smoking index (pack/years) and MnSOD enzyme activity (U/ml), (r = -0.33, P<0.001).