Cadmium (Cd2+), an environmental contaminant, has been shown to inhibit, even if not totally, natural killer (NK) cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) of human peripheral blood lymphocytes in a dose- and time-dependent manner. The presence of Cd2+ during the early period of the cytotoxic assay was needed to obtain maximal inhibition. Preincubation of either effector or target cells with Cd did not result in any inhibitory effect. Cd2+ also inhibited the cytotoxic activities of effector cells prestimulated with IL-2 for 18 h or 4 days, which mostly consist of NK cells. Our results indicate that Cd2+ did not block effector-target conjugate formation, but rather interfered with the hydrolysis of phosphoinositides, as shown by the decrease of inositol trisphosphate (IP3), which is known to release stored Ca2+.