Rabbit pulmonary macrophages were exposed in vitro to particulate lead oxide (PbO) for periods of up to 72 h and then assayed for the activity of tumor necrosis factor‐alpha (TNFα) released after stimulation with lipopolysaccharide (LPS). The levels of TNFa obtained from PbO‐treated cells were decreased in a dose‐dependent manner as compared with metal‐free control cells for each time point examined. Cells treated simultaneously with both LPS and PbO yielded less monokine than did cells receiving LPS alone. In addition, incubation of cell‐free TNFα with PbO resulted in a diminution of cytotoxicity directed against TNFα‐sensitive tumor target cells. Macrophage burdens of PbO particles increased with both the length of incubation and concentration of PbO used; increases in cellular lead burdens were paralleled by reductions in cell viability. Thus, under in vitro conditions, PbO affects the levels of the immunoregulatory monokine TNFα and also disrupts its cyto‐toxic properties after release from activated macrophages.