Three human cell lines of lymphoid (Molt-3 and Raji) or myeloid (HL-60) origin were maintained in vitro under zinc-sufficient or zinc-deficient conditions. Under these conditions, cell proliferation, viability and mode of death (apoptotic or necrotic) were assessed. All three cell types decreased their proliferative capacity and viability under conditions of zinc deficiency. Cell death in the HL-60 and Raji cultures occurred primarily via apoptosis, while most cells in zinc-deficient Molt-3 cultures died via necrosis. Apoptosis in zinc-deficient cultures of HL-60 and Raji cells was characterized by a slow decline in culture viability as cells with condensed and fragmented nuclear DNA appeared. These morphological changes were accompanied by an increase in cell buoyant density, which allowed separation of viable apoptotic cells from their non-apoptotic counterparts by means of percoll stepdensity gradients. Necrosis in zinc-deficient Molt-3 cultures was characterized by rapid loss of cell culture viability as these cells underwent direct lysis. Intact necrotic cells were easily identified by the flocculated state of their chromatin as well as the decreased basophilia of their cytoplasm. Analysis of DNA from apoptotic HL-60 and Raji cells revealed that internucleosomal DNA degradation, indicative of endogenous endonuclease activation, had occurred, whereas the nuclear DNA of necrotic Molt-3 cells remained relatively unfragmented. The different modes of cell death evoked may reflect the relative sensitivities of cells of these lineages to zinc levels in vivo.