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The XRCC3 protein participates in DNA double-strand breaks and recombinational repair. A single C-to-T nucleotide change at codon 241 (Thr241Met) has been identified in the XRCC3 gene. Using a hospital-based case–control approach, the authors studied the XRCC3 polymorphism as a possible genetic risk factor for lung carcinoma in African Americans and Mexican Americans. A total of 112 patients with lung carcinoma were frequency matched with 190 control participants on the basis of age, gender, and ethnicity. Polymerase chain reaction-restriction fragment length polymorphism molecular analysis was used successfully to identify the XRCC3 polymorphism in peripheral blood lymphocytes. No significant association between the XRCC3 variant allele polymorphism (odds ratio [OR], 1.25; 95% confidence interval [95% CI], 0.72–2.15) and lung carcinoma risk was noted. However, a significantly increased risk for lung carcinoma (OR, 5.20; 95% CI, 1.59–17.03) was evident in heavy smokers with the variant T-allele genotypes. Furthermore, a joint effect of the T-allele and heavy smoking was observed (OR, 37.31; 95% CI, 11.43–121.72). The XRCC3 polymorphism appeared to be associated with increased risk of lung carcinoma in certain subgroups. It is plausible that the association is very heavily dependent on the degree of smoking. Further studies with larger sample sizes will be necessary to confirm these findings. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11692