Reduced DNA repair capacity may influence susceptibility to lung cancer. XRCC1 plays an important role in base excision repair and in rejoining DNA strand breaks. In the XRCC1 gene, two common polymorphisms induce amino acid changes in codon 194 and codon 399 and correlate with levels of genotoxic damage. We examined the relation between these two polymorphisms and susceptibility to lung cancer among 334 incident cases and 704 population controls of African-American and Caucasian ethnicity in Los Angeles County, California. African-American and Caucasian subjects smoking 20+ cigarettes/day and carrying at least one copy of the codon 194 variant allele were at somewhat decreased risk of lung cancer (African-Americans OR=0.2, 95% CI 0.1-0.9; Caucasians OR=0.5, 95% CI 0.2-1.1). Similarly, for the codon 399 polymorphism, there was some evidence of a decreased risk for the homozygous variant genotype among heavier smokers (African-Americans OR=0.3, 95% CI 0.0-2.9; Caucasians OR=0.4, 95% CI 0.2-1.0). These results suggest that genetic variation in XRCC1 might contribute to lung cancer and may interact with the amount smoked.