Biomarkers for increased cytogenetic damage in smokers include sister chromatid exchanges (SCE) in peripheral lymphocytes and micronuclei in sputum cells. These markers may reflect increased cancer risk. Increased cancer risk has also been associated with lower blood levels of the antioxidants beta-carotene and vitamin C and with genetic deficiency of the detoxification enzyme glutathione S-transferase mu (GST-mu). We therefore evaluated the associations of plasma antioxidants, GST-mu phenotype, and indices for tobacco exposure with SCEs and micronuclei in a group of 156 male cigarette smokers and 38 nonsmokers. As expected, smokers as compared with nonsmokers had higher SCE levels (5.08 versus 4.71 SCE/lymphocyte) and lower levels of plasma beta-carotene (0.31 versus 0.48 mumol/liter) and blood vitamin C (36.6 versus 33.8 mumol/liter). In smokers, SCEs were weakly correlated with plasma cotinine (r = 0.186) but not with plasma antioxidants (all r < 0.04). Micronuclei in smokers were not correlated with either cotinine or antioxidants (all r < 0.14). As reported previously, SCEs were higher (5.24 versus 4.97 SCE/lymphocyte) in GST-mu-deficient smokers than in nondeficient smokers. Micronuclei, however, were similar in both GST-mu phenotypes (4.3 versus 4.9 micronuclei/3000 cells). No correlation was observed between micronuclei and SCEs (r = -0.025). Large random variations in both SCEs and micronuclei make it difficult to interpret the absence of relations unambiguously. The results indicate that SCEs and micronuclei have only limited sensitivity to variations in cigarette smoke exposure. The association between GST-mu and cancer risk may be mediated through increases in certain forms of smoking-induced DNA damage in GST-mu deficiency.