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Studies were designed to demonstrate whether red cells (RBCs) lose membrane segments in vivo. Plasma separated from fresh blood collected in citrate-phosphate-dextrose-adenine-one was passed through 0.8 mu nitrocellulose filters to remove residual RBCs and formed elements. Exocytic vesicles were separated by centrifugation at 70,000 × g. Transmission electron microscopy showed vesicles 50 to 200 nm in diameter which contained hemoglobin. Sodium dodecyl sulfate- polyacrylamide gel electrophoresis of vesicle membranes showed that spectrin bands 1 and 2 and ankyrin band 2.1 were absent. These observations are the initial demonstration that RBCs shed exocytic vesicles in the normal circulation.