It has been reported that in many neoplastic diseases, including leukemia, alterations in plasma zinc levels may frequently occur, although the causes for such alterations have yet to be clearly defined. Since zinc is required to induce biological activity to thymulin (Zn-FTS), a biochemical defined thymic hormone, and marginal zinc deficiencies may prevent its peripheral biological activation, we investigated the plasma level of zinc and of both active thymulin (Zn- FTS) and total zinc saturable thymulin (Zn-FTS + FTS) in 91 young patients affected by acute lymphoblastic leukemia (ALL) at various stages of the disease. It was discovered that the plasma zinc level was reduced at the onset and relapse, whereas in complete remission and in off-therapy it was in the normal range. Total zinc-saturable thymulin concentration did not change during the disease, whereas the active fraction was reduced at the onset and in relapse when compared with values observed in the other stages of the disease or in healthy controls. These data suggest that zinc plasma deficiency is present in ALL patients at the onset and during relapse, and that such a deficiency causes a decrease in the activity of thymulin despite a nearly normal production by the thymus. An impairment of peripheral immune efficiency in ALL patients is commonly found. The existence of positive correlations between zinc or active thymulin and peripheral immunological parameters (phytohemagglutinin [PHA] and concanavalin A [ConA]) at various stages of the disease suggests a link between derangement of peripheral immune function, thymic hormone activity, and zinc failure. These findings, considered together, suggest the possibility of a carefully controlled clinic trial with zinc in ALL patients at the onset and in relapse even in the light of in vitro ineffectiveness of physiological zinc or thymulin concentrations on the duplicative index of human lymphoblastoid cells.