GSTP1 and GSTM1 are genes involved in Phase II metabolism, whereas p53 is a tumor suppressor gene. Individually, functional polymorphisms of these genes have been studied as risk factors for lung cancer. Small sample sizes have hindered the detection of possible increases in risk associated with having two or more "at risk" polymorphisms of these three genes. In a large Caucasian population, we examined the association of combined variant genotypes [or double-variants (DVs)] of these three genes and lung cancer risk, compared with their corresponding "double-wild-type" genotypes. Because these DVs may promote lung carcinogenesis at an earlier age, a subgroup of individuals aged 55 years or younger was examined separately. Using a case-control design, individuals were genotyped for GSTM1, GSTP1, and p53 codon 72 using PCR-RFLP techniques. All of the analyses used multiple logistic regression. Indicator variables were created to evaluate the risk for individuals with the following DVs: GSTP1 GG + GSTM1-null and GSTP1 GG + p53 Arg/Pro or Pro/Pro. A total of 1694 cases and controls were evaluated. In the whole population, those with the double variants have a higher risk of lung cancer when compared with those with the double-wild-type genotypes, supporting our original hypothesis. Individuals with the GSTP1 and GSTM1, DV (P1-M1 DV) had a marginally significant higher risk of lung cancer compared with their double-wild-type counterparts [adjusted odds ratio (AOR), 1.60; 95% confidence interval (CI), 0.95-2.70]. A significantly higher risk was found for the GSTP1, p53 DV (P1-p53 DV; AOR, 1.99; 95% CI, 1.12-3.53). Among individuals aged 55 or younger, these risks were even higher: for the P1-M1 DV the AOR was 4.03 (95% CI, 1.47-11.1); for the P1-p53 DV the AOR was 5.10 (95% CI, 1.42-18.30). Specific DVs of GSTM1, GSTP1, and p53 codon 72 are associated with a higher lung cancer risk. This susceptibility is highest among younger individuals.