Immune cells and platelets maintain plasma membrane phospholipid asymmetry. Upon activation, this asymmetry is disrupted by phospholipid scrambling (PS), which is a major step during activation of immune cells, hemostasis and apoptosis. Anoctamin 6 (Ano6; TMEM16F) causes chloride (Cl−) and cation currents and is required for Ca 2+-dependent PS. It is defective in blood cells from patients with Scott syndrome, a rare bleeding disorder. We examined if Cl− currents and PS are related, whether both processes are Ca 2+ dependent, and whether Ca 2+-independent scrambling during intrinsic and extrinsic apoptosis is controlled by Ano6. Ca 2+ increase by ionomycin activated Ano6 Cl− currents and PS in normal lymphocytes, but not in B-lymphocytes from two different patients with Scott syndrome. Fas ligand (FasL) did not increase intracellular Ca 2+, but activated Cl− currents in normal but not in Scott lymphocytes. Whole-cell currents were inhibited by Cl− channel blockers and by siRNA knockdown of Ano6. In contrast, intrinsic mitochondrial apoptosis by ABT-737 did not induce Cl− currents in lymphocytes. PS was not inhibited by blockers of Ano6 or removal of Cl− ions. Remarkably, Ca 2+-independent scrambling due to extrinsic (FasL) or intrinsic (ABT-737) apoptosis was unchanged in Scott cells. We conclude that:(i) Ano6 Cl− currents are activated by increase in cytosolic Ca 2+, or Ca 2+ independent by stimulation of Fas receptors;(ii) Ca 2+-dependent PS induced by Ano6 does not require Cl− currents;(iii) Ca 2+-independent PS does not require Ano6;(iv) Ano6 is necessary for Ca 2+-dependent PS, but not by increasing intracellular Ca 2+.