The P2X7 receptor is expressed on T cells, however knowledge of its presence and function on human CD4+ and CD8+ subsets is limited. Immunolabeling with an anti-human P2X7 monoclonal antibody and flow cytometry demonstrated that P2X7 is present on the cell-surface of peripheral blood CD4+ and CD8+ T cells. Time-resolved flow cytometry demonstrated that extracellular ATP induced ethidium+ uptake into both T cell subsets. Flow cytometric measurements also demonstrated that ATP induced the rapid loss of CD62L (L-selectin) from CD4+ and CD8+ T cells. ATP-induced ethidium+ uptake and CD62L shedding were dramatically impaired in CD4+ and CD8+ T cells homozygous for the Glu496Ala loss-of-function single nucleotide polymorphism in the P2RX7 gene, demonstrating that both processes were a result of P2X7 activation. In summary, these results show that both human CD4+ and CD8+ T cells express P2X7 receptors, and that ATP activation of this receptor can lead to the rapid shedding of CD62L from these cells.