Although biochemical and immunologic aspects of mild or marginal human zinc deficiency have been well characterized, there is a paucity of data regarding the effects of prolonged marginal zinc deficiency on zinc homeostasis. It appears that human beings are able to maintain zinc homeostasis by increasing efficiency of zinc absorption and decreasing endogenous excretion of zinc when they are subjected to short-term dietary zinc restriction. However, a mild deficiency of zinc in human beings under usual circumstances is an outcome of chronic exposure to diets low in zinc lasting for many months and years. Therefore, it is important to determine whether or not the adapted zinc homeostasis during the short duration of dietary zinc deprivation is also maintained during a prolonged period of dietary zinc restriction. We assessed the efficiency of zinc absorption as well as endogenous zinc excretion during a 6-month period of dietary zinc restriction (63.1 mumol/day) in human volunteers by using a stable zinc (70Zn). Prolonged marginal zinc deficiency did not impair the functional role of endogenous zinc excretion in zinc homeostasis, but efficiency of zinc absorption was not sustained and decreased in the majority of our volunteers when the zinc-restricted diet was continued for 6 months. Such altered mechanisms of zinc homeostasis suggest that chronic human zinc deficiency warrants reassessment of dietary zinc requirement to preserve normal zinc status in the subsets of population that are vulnerable to zinc deficiency.