We used flow cytometry to observe the changes in T cell populations resulting from zinc deficiency in subjects with sickle cell anemia (SCA) and in healthy human volunteers without SCA. Zinc deficiency was associated with significant decreases in cellular zinc concentration, CD4+/CD8+ ratio, and percentage of CD73+ cells in the CD8+ population. The decrease in the percentage of CD73+ cells in the CD8+ subset was significantly correlated with lymphocyte zinc concentration and was accompanied by essentially no change in the percentage of CD11b+ cells in the CD8+ subset. Daily oral zinc supplementation in nine zinc-deficient human volunteers (25 mg elemental zinc) and in seven zinc-deficient SCA subjects (50 mg elemental zinc) resulted in increases in the absolute lymphocyte count and significant increases in the CD4+/CD8+ ratio and in the percentage of CD73+ cells in the CD8+ subset. In zinc-supplemented subjects, the increase in the percentage of CD73+ cells was accompanied by a significant decrease in the percentage of CD11b+ cells in the CD8+ subset. Changes in the CD4+/CD8+ and CD73+/CD11b- cell ratios in the CD8+ subset after treatment may provide a useful diagnostic criterion for zinc deficiency in humans.