To investigate the effect of cigarette smoking on mitochondrial DNA (mtDNA) mutation and lipid peroxidation in lung tissues, 152 samples from lung resections were collected. A novel deletion of 4,839 bp of mtDNA was found in 80 (52.6%) of the 152 lung samples. The breakpoints of the 4,839-bp mtDNA deletion were flanked by a nine-nucleotide direct repeat (5'-CATACACAA-3'). The frequency of occurrence and the proportion of the 4,839-bp mtDNA deletion in the lung increased significantly with the smoking index in terms of pack-years (P < 0.05). The incidence and proportion of the 4,839-bp mtDNA deletion in the lung tissues of current smokers were significantly higher than in those of nonsmokers (P < 0.05). In addition, we found that the content of lipid peroxides in the lung tissues of the smokers was significantly higher than in that of nonsmokers, and increased with the smoking index. The average malondialdehyde level in the lung tissues was 12.81 +/- 4.99 micromol/g for subjects with a smoking index of more than 50 pack-yr, and was 5.39 +/- 0.48 micromol/g for nonsmokers (P < 0.05). Multiple regression analysis showed that the smoking index, tissue lipid-peroxide content, and FEV1/FVC ratio were correlated with the proportion of the 4,839-bp mtDNA deletion in the lung. These results suggest that cigarette smoke plays an important role in the increase in mtDNA mutation and lipid peroxidation in the lung tissues of smokers.