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The primary objective of this study is to identify prognostic site-specific epigenetic changes in surgically treated Stage I and II nonsmall cell lung cancer (NSCLC) patients by quantifying methylation levels at multiple CpG sites within each gene promoter. Paraffin-embedded tumors from stage Ib, IIa and IIb in training and validation groups of 75 and 57 surgically treated NSCLC patients, respectively, were analyzed for p16, MGMT, RASSF1, RASSF5, CDH1, LET7, DAPK andPTENpromoter hypermethylation. Hypermethylation status was quantified individually at multiple CpG sites within each promoter by pyrosequencing. Molecular and clinical characteristics with time to recurrence (TTR) and overall survival (OS) were evaluated. Overall average promoter methylation levels ofMGMTandRASSF1 were significantly higher in smokers than in nonsmokers (p= 0.006 andp= 0.029, respectively). Methylation levels of the p16 promoter were significantly higher in squamous cell carcinoma than in adenocarcinoma (p= 0.020). In univariate analysis, hypermethylation ofRASSF1at CpG sites −53 and −48 andPTENat CpG site −1310 were the significantly associated with shorter TTR (p= 0.002 andp< 0.000, respectively). Hypermethylation ofPTENat −1310 andDAPKat −1482 were most significantly associated with outcome in multivariate analysis. These results show that methylation of specific promoter CpG sites inPTEN, RASSF1andDAPKis associated with outcome in early stage surgically treated NSCLC.