Animal studies have shown that tobacco smoke can induce lung cancer in mice,and that the intake of Vitamin E (VE) has a protective effect against its risk. However, the mechanisms of action of VE remain unclear. In this study, DNA microarrays for gene expression profiles of the mouse genome were applied in order to screen for the upregulated genes associated with VE intervention in smoke-induced lung cancer. Real-time PCR was used to validate the screened upregulated angiopoietin-3 gene (Ang-3), and Western blotting was used to investigate the expression of the Ang-3 protein. Our results demonstrate that smoking and VE intervention involve 621 upregulated genes, including oncogenes, non-oncogenes with clear function and genes with unclear function. Of these, Ang-3 presented high expression in both the smoking and tumor groups. Real-time PCR and Western blotting further indicated that smoking could upregulate the expression of Ang-3; moreover, Ang-3 was overexpressed in lung cancer tissue. VE intervention decreased its expression to some extent. This illustrates that Ang-3 may play an important role in the carcinogenesis and development of smoke-induced lung cancer, and could also be a target in lung cancer treatment.