Lung cancer is the leading cause of cancer mortality worldwide and tobacco smoking has been established as its biggest risk factor. Cigarette smoke contains several carcinogens. Most of them need to be activated by phase I enzymes, such as cytochrome P450 (CYP), while phase II enzymes, such as glutathione S-transferases are responsible for the detoxification of activated forms. The present study aimed to determine the role of CYP1A1, GSTP1 and GSTM1 gene polymorphisms in smoking-related lung cancer risk. It also aimed to investigate the association of the above polymorphisms with clinicopathological parameters, as well as their effect on survival. One hundred newly diagnosed lung cancer patients with advanced disease and 125 healthy controls with a smoking history participated in the study. The participants were screened for the presence of the following polymorphisms: MspI (CYP1A1), Ile105Val (GSTP1) and GSTM1 deletion. The above polymorphisms were also examined with regards to gender, age, histological type and survival. GSTP1 Ile/Val and GSTM1-null genotypes were associated with increased lung cancer risk and the presence of the combination of the three non-wild-type genotypes increases susceptibility to lung cancer (OR 3.328, 95% CI=1.681-6.587, p=0.001). In the non-small cell lung cancer group, the GSTP1 homozygous variant was significantly associated with increased lung cancer risk (p=0.008) and shorter survival. The results of this study suggest that the GSTP1 Ile/Val genotype and GSTM1 deletion contribute to increased lung cancer susceptibility. Moreover, GSTP1 Val/Val genotype is associated with increased lung cancer risk and shorter survival in non-small cell lung cancer patients.