Polymorphisms in inherited metabolic traits and intake of dietary antioxidants have been reported to be associated with risk for the development of lung cancer in smokers. This increased risk of lung cancer is presumably attributable to the accumulation of DNA damage. We conducted a study to investigate whether genetic metabolic variants and antioxidant consumption affected the sister chromatid exchange (SCE) level in lymphocytes. Study subjects were 78 friends and spouses of cases from a case-control study of lung cancer designed to investigate the association of metabolic polymorphisms with lung cancer. The metabolic traits studied included glutathione S-transferase class mu and variants of P-450 isoenzymes CYP1A1 and CYP2D6. Intake of antioxidants including vitamins A, C, and E and selenium was determined through the administration of a validated, semiquantitative food frequency questionnaire. Detailed information on smoking, family history of cancer, medical history, and environmental and occupational exposures was also obtained in an interviewer-administered questionnaire. Smoking status was found to be significantly associated with SCE frequency. In addition SCE frequency decreased with the period of time since quitting smoking. The presence of one or more glutathione S-transferase class mu alleles was associated with significantly lower SCE. Higher intake of vitamin A and selenium was also inversely associated with SCE level. Thus, the results suggest that glutathione S-transferase class mu and the intake of vitamin A and selenium may modulate the accumulation of chromosomal damage in lymphocytes.