AbstractLow natural killer (NK) responders selected from a panel of 600 normal, healthy volunteers exhibited 5‐ to 10‐fold less cytotoxicity against the human erythroleukemic cell line K562, compared with high NK responders. Antibody‐dependent cellular cytotoxicity against tumor cells, which is mediated by similar or identical effectors, was also depressed in low NK donors whereas lectin‐dependent T cell killing and monocyte‐mediated cytolysis of tumor cells was normal. Low NK donors exhibited normal frequencies of cells expressing the HNK‐1 marker of human NK cells and highly enriched NK fractions were not impaired in their ability to recognize and bind to NK‐sensitive target cells. Interferon partially activated low responder NK cells but did not restore the response to normal levels. The burst of chemiluminescence that is generated by NK cells within seconds of target cell contact was markedly impaired in low NK responder donors. We have previously shown that chemiluminescence detects reactive oxygen intermediates which are necessary but not sufficient for the activation of the NK cyto