Human erythrocytes were incubated at alkaline pH. In samples equilibrating within 60 min to pH 11 erythrocytes underwent prelytic vesiculation (fragmentation). Erythrocytes developed large (diameter often 1-2 µm) hemoglobin-filled blebs which could be released to the outer medium as hemoglobin containing vesicles. It is suggested that the described vesiculation at high pH occurs due to an uncoupling of the membrane skeleton from the lipid bilayer. Due to the uncoupling from the skeleton the erythrocyte lipid bilayer may behave similar to the membrane of a giant lipid vesicle.