Natural killer (NK) cells are a subpopulation of lymphocytes capable of killing a variety of tumor targets. They can limit pulmonary metastases in vivo and thus might be important effectors of tumor defense in human lung. Lymphocytes were purified from whole lung specimens obtained from patients with lung cancer undergoing curative resection, and their NK activity was compared with that of lymphocytes purified from normal lung specimens obtained from cadavers undergoing medicolegal autopsy. The NK activity of pulmonary lymphocytes obtained from the patients with lung cancer was significantly lower (p less than 0.05) than the NK activity of normal lungs. This reduction occurred despite high levels of blood NK activity in the patients with cancer, suggesting that NK cells might be locally suppressed in the lungs of patients with bronchogenic carcinoma. Because human pulmonary macrophages (PM) are known to be potent inhibitors of NK function, we investigated the role that PM might play in the reduction of NK activity in these patients. The PM obtained from the patients with lung cancer released soluble inhibitors of NK activity when stimulated with lipopolysaccharide. Release of these inhibitors was blocked by indomethacin, strongly suggesting a role for arachidonic acid metabolites as an inhibitor of pulmonary NK function. Inhibition of NK function by PM may occur in vivo, as a significant inverse correlation (r = -0.71, p less than 0.001) existed between the NK activity of lymphocytes obtained from a lung and the number of PM present in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)