Telomeres play a key role in the maintenance of chromosome integrity and stability. There is growing evidence that short telomeres induce chromosome instability and thereby promote the development of cancer. We investigated the association of telomere length and the risk of lung cancer. Relative telomere length in peripheral blood lymphocytes was measured by quantitative polymerase chain reaction in 243 lung cancer patients and 243 healthy controls that were frequency-matched for age, sex and smoking status. Telomere length was significantly shorter in lung cancer patients than in controls (mean +/- standard deviation: 1.59 +/- 0.75 versus 2.16 +/- 1.10, P < 0.0001). When the subjects were categorized into quartiles based on telomere length, the risk of lung cancer was found to increase as telomere length shortened (P(trend) < 0.0001). In addition, when the median of telomere length was used as the cutoff between long and short telomeres, individuals with short telomeres were at a significantly higher risk of lung cancer than those with long telomeres (adjusted odds ratio = 3.15, 95% confidence interval = 2.12-4.67, P < 0.0001). When the cases were categorized by tumor histology, the effect of short telomere length on the risk of lung cancer was more pronounced in patients with small cell carcinoma than in those with squamous cell carcinoma and adenocarcinoma (P = 0.001, test for homogeneity). These findings suggest that shortening of the telomeres may be a risk factor for lung cancer, and therefore, the presence of shortened telomeres may be used as a marker for susceptibility to lung cancer.