We have previously investigated the role of polymorphic chemical metabolizing genes in the susceptibility to the development of lung cancer using 110 primary lung cancer patients and 119 matched smoker controls [Cajas-Salazar et al.  Cancer Genet Cytogenet 145:97–102; Cajas-Salazar et al.  Int J Hyg Environ Health 206:473–483]. Together with data from the present study on DNA repair genes, we did not observe significant associations between any single variant genotype for several DNA-repair and chemical-metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or EPHX1]) and lung cancer. In the present study, we have further evaluated a nested group of 79 patients and 69 matched controls, and observed that increased chromosome aberrations (CAs) were associated with variant DNA-repair genotypes among both the patient and the control groups, with a significant increase for individuals having the XPD Lys/Gln + Gln/Gln genotypes (P = 0.046). Patients often had significantly increased CAs compared with controls with the same DNA-repair genotype and with similar cigarette smoking habits (≤40 pack-years or >40 pack-years). Analyses of interactions between the DNA-repair and chemical-metabolizing genes indicated that the most significant interactions were between the repair genotypes and the GSTM1/T1 null genotypes. Significant increases in CA from the interactions were often observed among patients with ≤40 pack-years, but not among those with >40 pack-years. Since some variant DNA-repair genotypes have functional deficits for DNA repair [Au et al.  Environ Health Persp 111:1843–1850], the association between variant DNA-repair genotypes and increased CAs suggests a risk mechanism for the development of lung cancer, with the DNA-repair genotypes interacting with variant chemical metabolizing genotypes to further increase the risk. The observation that patients had significantly increased CA frequencies compared with controls, irrespective of genotype, suggests that patients have additional factors that contribute to the development of lung cancer. Environ. Mol. Mutagen. 44:74–82, 2004. © 2004 Wiley-Liss, Inc.