Cigarette smoke components have a proven negative influence on human health. Adverse metabolic effects were observed in tissues and single cells. T lymphocytes get in contact with affected organs (e.g., lung) or cells (e.g., erythrocytes), as well as with smoke components and bioactive molecules, whose production is triggered by tobacco smoke. We therefore compared the gene expression profiles in these cells of the adaptive immune system of three male heavy smokers and three male nonsmokers using rapid T cell isolation and Affymetrix GeneChip HG U133A 2.0 microarray analysis. Eighty-eight genes were found to be significantly (t test) differentially expressed by a factor of 1.5-fold or larger between smokers and nonsmokers. Using the gene function groups of the gene ontology consortium to categorize the functions of the differentially expressed genes, the group termed "response to stimulus" was found to be most significantly affected by smoking. Our data indicate a prominent role of cytotoxic T lymphocytes in response to smoking. Several genes that are typically expressed in these cells were found regulated although the ratio of cytotoxic and helper T lymphocytes remained unchanged in smokers. Our data show that, in principle, it might be possible to identify health-related biomarkers in the transcriptome of T lymphocytes.