Natural killer (NK) cells are non-B, non-T lymphocytes that effect spontaneous cytolysis of both virus-infected and neoplastically transformed target cells. These NK lymphocytes have been detected in several species including man. Interferon is a primary regulator of natural killer activity. Because NK cells have been implicated in the regulation of tumour cell expression and can be induced by interferon in murine models, we have studied patients receiving large doses of interferon to determine (1) whether interferon could induce NK lymphocytes in the peripheral blood of man, and (2) whether there are characteristic kinetics for the appearance, disappearance and reactivation of NK lymphocytes following interferon therapy. We report here the activation of human NK cells by the systemic inoculation of human subjects with interferon. Five patients received interferon as therapy for non-Hodgkin's lymphoma. All showed a marked increase in NK cell activity 12--24 h after inoculation. Peak NK activity occurred 18 h after introducing interferon, and thereafter declined rapidly but remained above pre-interferon levels. Induced NK activity occurred with reintroduction of interferon but at lower levels of activity and with different kinetics.