Polymorphisms in DNA-repair genes could contribute to the interindividual differences in cancer susceptibility in smokers. By reducing DNA-repair capacity, these polymorphisms may influence the net level of smoking-induced genetic damage significantly, a critical step in the cascade of events leading to cancer. In this biomonitoring study, we examined the relationship between polymorphisms in the DNA-repair gene XPD/ERCC2 and genetic damage. We tested the hypothesis that coding polymorphisms in XPD/ERCC2 limit DNA-repair efficiency in humans leading to increased frequencies of chromosome aberration (CA) in their lymphocytes. We also used the mutagen-sensitivity assay, with the tobacco-specific nitrosamine NNK as a model mutagen, to determine whether lymphocytes from individuals with the variant XPD alleles are more sensitive to this tobacco-specific carcinogen. We calculated odds ratios (ORs) as estimates of relative risk of increased frequencies of CA associated with two XPD polymorphisms (Asp312Asn in exon 10 and Lys751Gln in exon 23). We observed a 2.57-fold (95% confidence limit [CL] = 0.88–7.50; P = 0.10) increase in risk of elevated in vivo frequencies of CA associated with the variant 312Asn allele in the total population. The relative risk was more pronounced in smokers (OR = 4.67; 95% CL = 1.04–20.90; P = 0.04) and in all subjects >48 years old (OR = 7.33; 95% CL = 1.53–35.10; P = 0.01). Similarly, elevations in NNK-induced aberrations were significantly associated with the 312Asn allele (OR = 3.69; 95% CL = 1.29–10.56; P = 0.02). The risk was higher in smokers (OR = 4.62; 95% CL = 1.14–18.70; P = 0.04) and in subjects >48 years old (OR = 5.76; 95% CL = 1.30–25.41; P = 0.03). No significant effect was observed with the 715Gln variant allele in relation to either in vivo or NNK-induced CA. These data suggest that the Asp312Asn polymorphism may alter the phenotype of the XPD protein, resulting in reduced DNA-repair capacity. Environ. Mol. Mutagen. 44:65–73, 2004. © 2004 Wiley-Liss, Inc.