Epigenetic silencing of E-cadherin via aberrant methylation has been investigated in various human tumors, whereas evidence for elucidating mechanism underlying reduction of E-cadherin mRNA remains unclear in non-small cell lung cancer (NSCLC). The authors previously found that reduction of E-cadherin mRNA or protein expression has been frequently observed in NSCLC. In this study, the authors explore the contribution of E-cadherin methylation to the development and progression of NSCLC. The authors directly performed the bisulfite DNA sequencing to examine CpG methylation within the 5' CpG island of E-cadherin in 35 tumor and paired normal tissue specimens from patients with primary NSCLC. Then, the authors measured the level of E-cadherin mRNA by real-time quantitative polymerase chain reaction (PCR) analysis. Despite of reduction in E-cadherin mRNA by 65.7% (23/35) and presence of methylation by 28.6% (10/35) in tumors, the authors found no association of reduction of E-cadherin mRNA level with methylation of 19 sites from -181 to -9 bp located upstream from the translation start of E-cadherin in NSCLC. In conclusion, the authors provide no evidence for the presence of aberrant methylation sites of E-cadherin in tumors from patients with NSCLC, which can explain decrease of E-cadherin mRNA. Decrease in E-cadherin mRNA may be regulated by methylation-independent pathways in NSCLC.