Aims: Janus kinase 3, a membrane associated intracellular tyrosine kinase, is critically important for IL-2 receptor signalling. JAK3 is predominantly expressed in the haematopoetic tissues. The kinase plays a decisive role in T-lymphocyte activation, function and survival. JAK3 deficiency leads to (Severe) Combined Immunodeficiency (SCID) resulting from enhanced lymphocyte apoptosis. JAK3 is activated by phosphorylation at ⁹⁸⁰tyrosine. Hitherto nothing is known about expression and function of JAK3 in erythrocytes. The present study was thus designed to investigate the role of JAK3 in erythrocyte physiology. Methods: Western blotting, immunohistochemistry and confocal microscopy was utilized to determine JAK3 expression and phosphorylation in erythrocyte. Erythrocytes were energy depleted (by incubation in zero glucose ringer) or treated with the Ca²⁺ ionophore ionomycin (30min, 1mM) in the presence and absence of specific JAK3 inhibitors WHI-P131/JANEX-1 (156mM), WHI-P154 (11.2mM) and WHI-P97 (22mM) and FACS analysis utilized to determine cytosolic Ca²⁺ (Fluo3 fluorescence), phosphatidylserine exposure (annexin binding) and cell volume (forward scatter). Results: JAK3 is expressed in erythrocytes and phosphorylated following 24h and 48h glucose depletion. Glucose depletion increased cytosolic Ca²⁺, decreased forward scatter and annexin binding. The increase of Ca²⁺ and the annexin binding was significantly blunted by the specific JAK3 inhibitors WHI-P131/JANEX-1, WHI-P154 and WHI-P97. Treatment of erythrocytes with Ca²⁺ ionophore ionomycin (30min, 1M) similarly triggered annexin V binding and decreased forward scatter, effects, however, not significantly modified by WHI-P131/JANEX-1 or WHI-P154 or WHI-P97. Conclusion: JAK3 is expressed in erythrocytes, is activated upon energy depletion and plays an important role in suicidal erythrocyte death upon energy depletion. The observations thus disclose a novel role of Janus kinase 3 in the regulation of cell survival.