Chronic obstructive pulmonary disease (COPD) is associated with polygenic inheritance, but its pathogenesis remains unclear. To observe the mRNA expression profile in COPD, blood samples obtained from smokers with COPD and age-matched healthy smokers were analyzed by mRNA microarray, and then quantitative real-time PCR was performed for further validation of the mRNAs with differential expression in 100 COPD patients and 100 control subjects. 175 mRNAs were found to be significantly differentially expressed between two groups, with 147 mRNAs up-regulating and 28 mRNAs down-regulating. Among them, 10 mRNAs including 8 up-regulated mRNAs (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1, pleomorphic adenoma gene-like 2, fibrinogen like protein 2, phosphatase and tensin homolog, ras homolog family member A, ubiquitinconjugating enzyme E2D1, hypoxanthine phosphoribosyltransferase 1, and hypoxia inducible factor 1 and 2 down-regulated mRNAs (kruppel-like factor 4 and forkhead box O1) were most differentially expressed in COPD patients compared with those of healthy smokers. The expression of PLAGL2 validated by QRT-PCR was significantly higher in COPD patients than healthy smokers, and it indicated that overexpression of PLAGL2 might be associated with the pathogenesis of COPD.