The initial site of smoking-induced lung disease is the small airway epithelium, which is difficult and time consuming to sample by fiberoptic bronchoscopy. We developed a rapid, office-based procedure to obtain trachea epithelium without conscious sedation from healthy nonsmokers (n= 26) and healthy smokers (n= 19, 27 +/- 15 pack-year). Gene expression differences (fold change >1.5, p < 0.01, Benjamini-Hochberg correction) were assessed with Affymetrix microarrays. A total of 1,057 probe sets were differentially expressed in healthy smokers versus nonsmokers, representing >500 genes. Trachea gene expression was compared to an independent group of small airway epithelial samples (n= 23 healthy nonsmokers, n= 19 healthy smokers, 25 +/- 12 pack-year). The trachea epithelium is more sensitive to smoking, responding with threefold more differentially expressed genes than small airway epithelium. The trachea transcriptome paralleled the small airway epithelium, with 156 of 167 (93%) genes that are significantly up- and downregulated by smoking in the small airway epithelium showing similar direction and magnitude of response to smoking in the trachea. Trachea epithelium can be obtained without conscious sedation, representing a less invasive surrogate "canary" for smoking-induced changes in the small airway epithelium. This should prove useful in epidemiologic studies correlating gene expression with clinical outcome in assessing smoking-induced lung disease.