The response of erythrocyte metallothionein to dietary zinc in human subjects was evaluated in a controlled metabolic protocol including standard indices of zinc status. Fifteen male subjects, age 27 +/- 3.6 y, participated in a 90-d, four-phase study consisting of acclimation (7 d; 15 mg Zn/d), treatment (6 wk; either 3.2, 7.2 or 15.2 mg Zn/d), depletion (12 d; 0.55 mg Zn/d) and supplementation (30 d; self-selected diet plus 50 mg Zn/d) phases. During the treatment phase erythrocyte metallothionein decreased in the group fed 3.2 mg Zn/d. Erythrocyte metallothionein decreased during the depletion phase (46 +/- 10%) to below the normal concentration in all groups and increased in the supplementation phase. Plasma zinc concentration decreased in the group fed 3.2 mg Zn/d during the treatment phase relative to the acclimation phase. Erythrocyte zinc decreased in all groups during the depletion phase relative to the treatment phase, and then increased during the supplementation phase. These data suggest that erythrocyte metallothionein can be used as a measure of status in severe zinc depletion and that comparing the change in erythrocyte metallothionein over a 6-wk period can differentiate between low and adequate levels of dietary zinc intake.