The 5p15.33 locus has been recently identified to associate with multiple cancer types including lung, urinary bladder, prostate, and cervical cancer, based on its critical role in the maintenance of telomere, chromosome stability, and ultimately preventing normal cell malignance. TERT (human telomerase reverse transcriptase) is an attractive candidate gene for the 5p15.33 locus. Recently, a number of case-control studies have been carried out to investigate the relationship between the rs2736100 polymorphism in TERT and genetic susceptibility to lung cancer. However, the results have been inconclusive. To investigate this inconsistency and derive a more precise estimation of the relationship, we conducted a comprehensive meta-analysis of 56,223 cases and 86,680 controls from 22 published studies. Using the random-effects model, we found a significant association between rs2736100 polymorphism and lung cancer risk with per-allele OR of 1.20 (95% CI, 1.16-1.23; P < 10(-5)). Significant results were also observed using dominant and recessive genetic model. Significant results were found in East Asians and Caucasians when stratified by ethnicity in all genetic models. In addition, our data indicate that rs2736100 is involved in lung cancer susceptibility and confer its effect primarily in adenocarcinoma in the subgroup analyses by histological subtype. In the stratified analysis according to sample size, smoking behavior, sex, and age, risks significantly increased for the polymorphism. In conclusion, this meta-analysis demonstrated that TERT rs2736100 polymorphism is a risk factor associated with increased lung cancer susceptibility, particularly for lung adenocarcinoma.