We investigated whether lung cancer was associated with an increased micronucleus (MN) frequency in lymphocytes in a case-control study. Epidemiological data were obtained by an interviewer-administered questionnaire and included information on smoking history, intake of dietary micronutrients, general medical history, environmental and occupational exposures to mutagens and carcinogens, and family history of cancer. A modified cytokinesis-block method was used to determine individual MN frequency. Polymorphisms in glutathione S-transferase class mu were determined by PCR analysis. Overall, 55 controls and 42 cases were studied. MN frequency in cases and controls was not associated with age, smoking, metabolic genetic polymorphisms, environmental and occupational exposures, or medical history. Female controls had a significantly higher MN frequency than male controls (p = 0.05). Overall, MN frequency was significantly higher in cases than in controls (p < 0.01). Twenty-four cases (57%) had an MN frequency higher than the upper 95% confidence interval of the mean value for controls (11.5 MNs/1000 binucleated cells). Further analysis showed that, cases who were current and former smokers had significantly higher MN frequencies than controls (p = 0.04); this difference was not seen in the group that had never smoked. The significantly higher MN frequency among cases with a history of smoking may be attributable to the presence of lung neoplasm per se or to the interaction of smoking with endogenous factors associated with the development of lung cancer.