Lung adenocarcinoma (ADC) is one of the major histological types of lung cancer. Genetic polymorphism in DNA repair genes and lung ADC susceptibility is well documented. In this case-control study, the association between the polymorphic sites of DNA repair genes XPD-751, XRCC1-399, and OGG1-326, and lung ADC susceptibility in ethnic Han Chinese population has been investigated. Genomic DNA was isolated from the peripheral blood of 201 healthy controls and 82 lung ADC patients from the people of Hunan Province, China. Polymorphisms of the investigated genes were analyzed by using polymerase chain reaction-restriction fragment length polymorphism. There was no significant difference between the samples from lung ADC patients and healthy controls about the genotype frequencies of XPD-751, XRCC1-399, and OGG1-326 sites. However, multifactor dimensionality reduction analysis showed that the genetic polymorphisms of the three-loci models of DNA repair genes (XPD-751/XRCC1-399/ OGG1-326) are associated with lung ADC. Thus, this study reveals that a three-order interaction among the polymorphic sites of XPD-751, XRCC1-399, and OGG1-326 is associated with lung ADC risk in the studied population, although polymorphism in individual gene was not associated. © 2013 International Society of Oncology and BioMarkers (ISOBM).