PGE2 activates Ca2+-permeable cation channels in red blood cell (RBC) membranes leading to entry of Ca2+ with subsequent eryptosis, i.e. cell shrinkage, breakdown of phosphatidylserine (PS) asymmetry, and membrane blebbing, all features typical for apoptosis in nucleated cells. PS exposing cells are recognized by macrophages, engulfed, degraded and thus cleared from circulating blood. The present study explored whether lipoxygenase inhibitors influence eryptosis. As determined by competitive ELISA, lipoxygenase inhibitors nordihydroguaiaretic acid (NDGA, 50 mM) and Bay-Y5884 (20 mM) enhanced prostaglandin PGE2 release. According to whole-cell patch-clamp, NDGA (50 mM) and Bay-Y5884 (20 mM) activated nonselective cation channels. The effect of NDGA and Bay-Y5884 on cation channels was abolished by the cyclooxygenase inhibitor diclophenac (10 mM). NDGA (50 mM) and Bay-Y5884 (20 mM) significantly increased RBC free Ca2+ concentration and PS exposure as analyzed in flow cytometry by Fluo3 fluorescence and annexin-V binding, respectively. Both effects were blunted by cycloxygenase inhibitors acetylsali-cylic acid (50 mM) and diclophenac (10 mM). In conclusion, the lipoxyge-nase inhibitors NDGA and Bay-Y5884 enhance RBC PGE2 formation with subsequent activation of cation channels, Ca2+ entry and phospholipid scrambling.