Activation of the P2X7 receptor by the extracellular damage‐associated molecular pattern, adenosine 5′‐triphosphate (ATP), induces the shedding of cell surface molecules including the low‐affinity IgE receptor, CD23, from human leukocytes. A disintegrin and metalloprotease (ADAM) 10 mediates P2X7‐induced shedding of CD23 from multiple myeloma RPMI 8226 B cells; however, whether this process occurs in primary B cells is unknown. The aim of the current study was to determine whether P2X7 activation induces the rapid shedding of CD23 from primary human and murine B cells. Flow cytometric and ELISA measurements showed that ATP treatment of human and murine B cells induced the rapid shedding of CD23. Treatment of cells with the specific P2X7 antagonist, AZ10606120, near‐completely impaired ATP‐induced CD23 shedding from both human and murine B cells. ATP‐induced CD23 shedding was also impaired in B cells from P2X7 knockout mice. The absence of full‐length, functional P2X7 in the P2X7 knockout mice was confirmed by immunoblotting of splenic cells, and by flow cytometric measurements of ATP‐induced YO‐PRO‐12+ uptake into splenic B and T cells. The broad‐spectrum metalloprotease antagonist, BB‐94, and the ADAM10 antagonist, GI254023X, impaired P2X7‐induced CD23 shedding from both human and murine B cells. These data indicate that P2X7 activation induces the rapid shedding of CD23 from primary human and murine B cells and that this process may be mediated by ADAM10.