Using the representational difference analysis (RDA) technique on pooled mRNA of five primary lung adenocarcinomas and their corresponding non-neoplastic lung tissues, we identified six genes that were putatively overexpressed in this type of lung cancer. Five corresponded to previously isolated genes, while one (Lc19) matched with the sequence of an unannotated EST. Real-time RT-PCR analyses of expression levels in a panel of 34 paired primary non-small cell lung cancer (NSCLC) and corresponding grossly normal appearing lung tissues confirmed the common overexpression of these genes in non-small cell lung cancer. Among these genes, overexpression of Lc19, hyaluronan binding protein 2 (HABP2) and crystalline-mu appeared more specific to adenocarcinoma, whereas ceruloplasmin, integrin alpha-11 and collagen type XI alpha 1 were overexpressed at high frequency among both adenocarcinoma and squamous cell carcinoma. These genes represent novel candidate tumor biomarker genes for NSCLC and its histological subtypes.