Zinc deficiency alters lymphocyte and monocyte function in man and animals. A patient with isolated zinc deficiency was found to have lymphopenia (420 lymphocytes/microliter), depressed T-cell mitogen response (48% of normal control), increased numbers of circulating T-suppressor cells (OKT8 reactive cells) and decreased circulating T-helper cells (OKT4 reactive cells). Activity of the patient's natural killer (NK) cells was 1 lytic unit/10(6) cells (normal 10 to 40), and monocyte cytotoxicity (MC) was four times that of normal controls. Zinc repletion in vivo improved the peripheral lymphocyte count, corrected the abnormal OKT8-to-OKT4 ratio, normalized T-cell response to mitogen, improved NK function, and lowered MC to control values. A divalent cation chelator, 1,10-orthophenanthroline (OP), was used to simulate zinc deficiency in vitro. T-cells exposed to OP are nonresponsive to mitogen unless zinc is added. NK function of lymphocytes from normal donors exposed to OP was depressed in a time- and dose-dependent manner. NK activity of peripheral blood lymphocytes (PBL) from 12 normal donors exposed to 50 microM OP for 16 hr was 10.3 +/- 7 lytic units/10(6) cells (mean +/- S.E.M.) vs. 32.6 +/- 14 for cells incubated in medium alone. When monocytes were exposed for 16 hr to 50 microM OP, however, MC significantly increased to a range two to five times that of control. OP-induced alterations of lymphocyte and monocyte function was reversed by the addition of 50 microM zinc but not calcium or magnesium. Since NK activity and MC are thought to be important in host tumor immunity, alterations in zinc metabolism may have important implications for human tumor immune surveillance mechanisms.