AbstractWe have studied the effects of zinc on the51Cr survival of red blood cells (RBC) from patients with homozygous sickle cell anemia (SCA) using an animal model in which the RBC were transfused into specially prepared rats. The slope (λs) of a standard51Cr RBC survival curve was used as a measure of the rate of RBC sequestration.The effects of intravenous zinc were of considerable therapeutic interest from the standpoint of setting guidelines for effective blood levels of zinc in patients. SCA RBC were transfused into rats whose plasma zinc levels had been raised 3–6 times above normal (300–600 μg/100 ml) by prior iv injection of zinc acetate; in three experiments the mean λss in zinc‐treated animals breathing 15–16% oxygen was significantly lower (meaning lessened sequestration and greater survival) than saline‐treated controls. A possible explanation for the requirement to lower ambient oxygen tension in order to see this zinc effect is discussed.We have further observed an increased mean λsfor RBC from 10 SCA patients compared to 4 normal controls (0.134 vs 0.030; t = 2.8, p<0.01). The λsvalues are quite patient specific (4 patients studied; F = 18.2, p = 0.002). In vitro pretransfusion treatment of SCA RBC with 1.5 mM zinc resulted in a significant increase in hemoglobin oxygen affinity and a marked reduction in λs(0.073 vs 0.120; t = 4.5, p<0.01). The mean λswas not affected by in vitro 0.3 mM zinc treatment; this level did not change hemoglobin oxygen affinity.We conclude that systemic zinc therapy in the animal model described, at plasma levels only slightly higher than those presently obtained in patients, prolongs SCA RBC survival. This animal model is a sensitive measure of the sicklability of SCA RBC and is useful in the testing of in vitro and in vivo ant