The etiology of lung cancer in population with little or no tobacco exposure is not well understood. Individual genetic susceptibility factors have been suggested to contribute to lung cancer risk in this population. Mutations in the p53 tumor suppressor gene are implicated in the development of lung cancer as they are frequently found in lung tumors from both smokers and never-smokers. In order to determine whether genetic polymorphisms affecting DNA repair capacity modulate p53 mutations in lung tumors from never-smokers, we compared p53 mutations with genotypes of XPD 312, XPD 751, and XRCC1 399 in lung tumors from 43 lifetime never-smokers. p53 mutations were identified in 10 (23%) cases and consisted mostly of G/C to A/T transitions. No statistically significant association was found between p53 mutations and genotypes of XPD 312 or XPD 751. However, patients with the XRCC1 399 Gln allele, that results in a lower base excision repair capacity, were more likely to have p53 mutations, compared with patients the wild-type Arg allele (P = 0.03). In addition, the p53 mutation frequency increased with an increasing number of combined genotypes associated with a lower DNA repair capacity of XPD 312, XPD 751, and XRCC1 399 (P = 0.02). These results suggest that individuals who never smoked and had XRCC1 399 Gln allele may be at a greater risk of p53 mutations, especially if combined with the genotypes of XPD 312 and XPD 751 that may result in a lower DNA repair capacity.