We have found that natural killer (NK) cells were very active in pleural effusions containing Mycobacterium tuberculosis. Cytotoxicity against K562 and Raji was augmented when the mononuclear cells were cocultured for 18 hr with purified protein derivative (PPD) derived from M. tuberculosis culture supernatants. In pleural effusions of cancer patients, PPD-activated mononuclear cells were less cytotoxic than their counterparts in peripheral blood. However, in the same patients, interferon and interleukin-2 production was greater in pleural effusions than in peripheral blood. On the other hand, in tuberculosis patients there was no significant difference in cytotoxicity between peripheral blood and pleural effusion mononuclear cells, but the production of interferon and interleukin-2 was higher in pleural effusions than in peripheral blood. Neither group of patients consistently demonstrated a correlation between production of interferon or interleukin-2 in peripheral blood and cytotoxicity. Both PPD-induced cytotoxicity and the production of interferon and interleukin-2 were lower in mononuclear cells of carcinomatous than tuberculous pleural effusion. These results indicate that peripheral blood and pleural effusion mononuclear cells differ in cytotoxicity as well as in interferon and interleukin-2 production. Further, these activities also differ in tuberculous and carcinomatous pleural effusions.