We previously reported targeted overexpression of c-myc to alveolar epithelium to cause lung cancer. We now extended our studies to the serum proteome of tumor bearing mice. Proteins were extracted with a thiourea-containing lysis buffer and separated by 2-DE at pH 4-7 and 3-10 followed by MALDI-TOF/TOF analysis. Forty-six proteins were identified in tumor bearing mice of which n = 9 were statistically significant. This included disease regulated expression of orosomucoid-8, alpha-2-macroglobulin, apolipoprotein-A1, apolipoprotein-C3, glutathione peroxidase-3, plasma retinol-binding protein, and transthyretin, while expression of apolipoprotein-E was decreased at late stages of disease. Moreover, serum amyloid P component was uniquely expressed at late stages of cancer. It is of considerable importance that most disease regulated proteins carried the E-Box sequence (CACGTG) in the promoter of the coding gene, therefore providing evidence for their regulation by c-myc. Notably, expression of alpha-2-macroglobulin, transthyretin, alpha-1-antitrypsin, and properdin was in common in different lung tumor models, but regulation of orosomucoid-8, apolipoprotein-A1, apolipoprotein-C3, apolipoprotein-E, glutathione peroxidase-3, plasma retinol-binding protein, and serum amyloid P component was unique when the serum proteomes of c-myc and c-raf tumor bearing mice were compared. Therefore, candidate biomarkers to differentiate between atypical adenomatous hyperplasias (AAH) and bronchiolo-alveolar carcinomas (BAC)/papillary adenocarcinomas (PLAC) can be proposed.