Carbon nanotubes (CNTs) possess unique structural and functional properties and are readily internalized by various mammalian cells, making them highly attractive as a tool for gene and drug delivery. However, prior to us. e in vivo as carriers for therapeutics, their toxicity and potential to elicit an immune response need to be understood. To evaluate the acute response of blood leukocytes to CNTs in vitro, we recreated two specific events: (a) a direct-exposure event that may occur due to presence of CNTs in circulation and (b) presentation of CNTs to blood leukocytes via antigen presenting cells. The potential for activation of different leukocyte subpopulations was then evaluated by profiling various early activation markers using flow cytometry. To ensure relevance to gene and drug delivery, these experiments utilized single-walled CNTs (SWCNTs) functionalized with single-stranded (ss)-DNA fragments consisting of guanine-thymine (GT) repeat sequences, which have potential to serve as a backbone for transport of biomolecules and also as a surfactant to prevent aggregation. Results from this study demonstrate that ssDNA-functionalized SWCNTs does not elicit an acute immune response from blood leukocytes through either direct or indirect interactions as verified by the expression of early leukocyte activation markers. From the Clinical Editor: Carbon nanotubes offer a possible option for targeted gene and drug delivery, but first their toxicity and potential to elicit an immune response need to be understood. The authors of this study demonstrate that ssDNA-functionalized SWCNTs do not elicit an acute immune response from blood leukocytes as verified by the expression of early leukocyte activation markers. © 2011 Elsevier Inc.