P2X₇ is a receptor for extracellular nucleotides expressed by different normal cell types. P2X₇ triggering may result in stimulation of cell proliferation or induction of apoptosis depending on the level of activation. P2X₇ expression and function in B-cell chronic lymphocytic leukemia has been shown to correlate with disease severity. Here, we have asked the question of whether P2X₇ is expressed and functional in neuroblastoma, a pediatric tumor of neuroectodermal origin. P2X₇ was detected both in primary neuroblastoma tumors and in neuroblastoma cell lines. In the latter cells, P2X₇ stimulation by ATP was found to trigger (a) increased intracellular calcium fluxes, (b) plasma membrane depolarization, and (c) formation of a nonselective plasma membrane permeable pore. In contrast to the usual response typically observed in the majority of cell types, P2X₇ in vitro stimulation did not induce caspase-3 activation or apoptosis of neuroblastoma cells but rather supported their proliferation. Growth stimulation was partially due to substance P release from nucleotide-activated neuroblastoma cells. Therefore, neuroblastoma cells seem to have molded P2X₇ function to their advantage in two ways (i.e., by silencing P2X₇ proapoptotic activity and by coupling P2X₇ stimulation to release of locally acting trophic factors). (Cancer Res 2006; 66(2): 907-14)