DNA ligases catalyze the joining of single and double-strand DNA breaks, which is an essential step in DNA replication, recombination and repair. Recently, a common single nucleotide polymorphism (A-->C) in exon 6 of DNA ligase I (LIG1) was identified, but its functional relevance remains to be determined. Because LIG1 participates in DNA repair and reduced DNA repair capacity is associated with risk of lung cancer, we evaluated in a non-population-based case-control study of 530 lung cancer cases and 570 cancer-free controls the role of this polymorphism in susceptibility to lung cancer. All of the subjects were non-Hispanic whites and the controls were frequency-matched to cases on age, sex and smoking status. Using the polymerase chain reaction-restriction fragment length polymorphism method, we found that this LIGI A-->C substitution was very common in healthy controls and that the A and C allele frequencies were close to 0.5. However, there was no significant difference in the frequency distributions of LIGI genotypes between lung cancer cases and controls (25.7, 49.8 and 24.5% in cases and 26.1, 49.7 and 24.2% in controls for the AA, AC and CC genotypes, respectively). Therefore, there was no evidence to support an association between this polymorphism and the risk of lung cancer (adjusted odds ratio (OR)=1.06, 95% confidence interval (CI)=0.76-1.49 for AC versus CC and OR=0.93, 95% CI=0.64-1.36 for AA versus CC) neither in all cases nor in different histopathologic types. The results of this large case-control study suggest that this LIG1 polymorphism may not play an important role in susceptibility to lung cancer.