Tumor necrosis factor (TNF) is a monokine that is cytotoxic/cytostatic for a variety of tumor cells and has multiple effects on normal cells. We demonstrate that normal and malignant human myeloid cells express a single class of high-affinity receptors (400 to 1,900 per cell, KD 20 to 90 pmol/L) for TNF. Mitogen-stimulated lymphocytes have a similar number of TNF receptors, whereas resting lymphoid cells have fewer receptors. RBCs and platelets have no detectable TNF receptors. No correlation is observed between the receptor number, receptor affinity, and the cytotoxic effect of TNF on myeloid cell lines. Significant cytotoxic effects of TNF on the most sensitive myeloid cell line (HL-60 promyelocytes) could be seen at concentrations tenfold lower than those concentrations at which one half of the TNF receptors were occupied. Our data show that significant biologic effects of TNF can occur at low levels of receptor occupancy and resistance to TNF is not related to the absence of TNF receptors on certain myeloid leukemic cell lines.