Several polymorphic genes have been reported to be possibly involved in modifying lung cancer risk in smokers. The gene GSTM1 is frequently deleted in human populations, and the null genotype has been reported to be a risk factor for developing lung carcinoma. A germline polymorphism of p53 with a single-base change at codon 72 that causes an amino acid replacement of arginine (Arg; CGC) by proline (PRO; CCC) has also been reported to be associated with cancer susceptibility in a Japanese population. Both polymorphisms were genotyped by PCR in a northwestern Mediterranean healthy population (n = 147) and in a group of lung cancer patients (n = 139). The results showed that the frequency of the GSTM1 null genotype was higher in the lung cancer patients compared to the controls [odds ratio (OR), 1.57; 95% confidence interval (CI), 0.99-2.51]. The histological subtypes most clearly modified were small cell carcinoma (OR, 1.89; CI, 0.97-3.65) and adenocarcinoma (OR, 1.93; CI, 0.90-4.14). The null GSTM1 genotype was more frequent among those cancer patients who were medium/ light smokers (< or = 50 pack-years) and in those who showed an onset of the disease at a more advanced age. The study of the p53 polymorphism in the healthy population showed allele frequencies of 0.79 (Arg) and 0.21 (Pro). The frequencies found in the lung cancer patients were statistically similar. Both polymorphisms were studied together, and the relative risk of the combination null GSTM1 and Pro/Pro or Arg/Pro genotypes was calculated taking the combination of GTSM1 + together with Arq/Arg as a baseline. The OR found (1.97; CI, 1.03-3.73) suggests that the Pro allele of the p53 germline polymorphism may slightly increase the risk fo the GSTM1 null genotype among smokers.