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Upon proinflammatory challenges, endothelial cell surface presentation of the leukocyte receptor P-selectin, together with the stabilizing co-factor CD63, is needed for leukocyte capture and is mediated via demand-driven exocytosis from the Weibel-Palade bodies that fuse with the plasma membrane. We report that neutrophil recruitment to activated endothelium is significantly reduced in mice deficient for the endolysosomal cation channel TPC2 and in human primary endothelial cells with pharmacological TPC2 block. We observe less CD63 signal in whole-mount stainings of proinflammatory-activated cremaster muscles from TPC2 knockout mice. We find that TPC2 is activated and needed to ensure the transfer of CD63 from endolysosomes via Weibel-Palade bodies to the plasma membrane to retain P-selectin on the cell surface of human primary endothelial cells. Our findings establish TPC2 as a key element to leukocyte interaction with the endothelium and a potential pharmacological target in the control of inflammatory leukocyte recruitment. [Display omitted] • Endothelial two-pore channel 2 (TPC2) governs leukocyte capture on activated endothelium • Histamine activates TPC2 to release endolysosomal Ca2+ • TPC2 promotes CD63 loading onto Weibel-Palade bodies • These findings expand the molecular understanding of leukocyte-endothelium interactions Goretzko et al. report that the endolysosomal two-pore channel 2 (TPC2) affects leukocyte recruitment to activated endothelium. They find that TPC2 controls postendolysosomal trafficking of the P-selectin stabilizing co-factor CD63 to the Weibel-Palade bodies in endothelial cells, thus affecting CD63 and P-selectin cell surface presentation and leukocyte capture. [ABSTRACT FROM AUTHOR]