CD38 is a transmembrane glycoprotein involved as an orphan receptor in many physiological processes of lymphocytes. It is also a bifunctional enzyme that catalyzes at its ectocellular domain the synthesis from NAD⁺ (cyclase) and the hydrolysis (hydrolase) of the calcium‐mobilizing metabolite cyclic ADP‐ribose (cADPR). A still unexplained paradox concerns the relationship between ectocellular localization of CD38 and intracellular calcium‐releasing activity of its intermediate product cADPR. Incubation of CD38⁺ human Namalwa B cells with external NAD⁺ elicited extensive membrane down‐regulation of CD38 and its internalization in non‐clathrin‐coated vesicles. Since the internalized CD38 was demonstrated to be enzymatically active, this NAD⁺‐dependent process is a hitherto unrecognized means for shifting cADPR metabolism from the cell surface to the intracellular environment.