Natural killer (NK) cells are a subpopulation of lymphocytes capable of killing a variety of neoplastic targets. NK can limit pulmonary metastases in animal models and could be important mediators of tumor defense in human lung. Previous studies in humans have suggested, however, that pulmonary NK cells obtained by bronchoalveolar lavage (BAL) are functionally inert. We purified lymphocytes from human lung tissue and compared the NK activity of these cells with lymphocytes purified from peripheral blood. The activity of NK cells obtained from minced whole lung specimens was comparable to that found in peripheral blood. Monoclonal antibodies to 2 markers found on peripheral blood large granular lymphocytes (LGL) were utilized to determine the phenotype of pulmonary NK cells. Lymphocytes expressing Leu 11b were responsible for pulmonary NK activity as all NK function was abrogated by pretreatment with anti-Leu 11b and complement. In contrast, lymphocytes expressing Leu 7 had little NK activity. Although the frequency of lymphocytes expressing Leu 7 or Leu 11 in blood was comparable, there were significantly more (p less than 0.001) Leu 7+ lymphocytes in the lung than Leu 11+ cells. Immunofluorescent staining of lung tissue demonstrated that LGL expressing Leu 11 were confined largely to the lung interstitium, whereas LGL expressing Leu 7 were frequently located in alveoli and larger airways. These findings suggest that NK function is present in the human lung and that it is compartmentalized with the NK-active Leu 11+ lymphocytes located primarily in the lung interstitium.