The HNK-1 monoclonal antibody detects an antigen (Leu-7) on a subpopulation of large granular lymphocytes which have natural killer cell function. Recently this antigen has been found on nonhemopoietic tissues. In the present study human lung tumor cells were examined for the presence of Leu-7 antigen using an enzyme-linked immunosorbent assay, immunoperoxidase staining, and fluorescence-activated cell sorter analysis. All small cell lung tumor cells tested were Leu-7 positive. In contrast only two of seven biopsy specimens from small cell lung cancer patients were Leu-7 positive. Several large cell lung tumor lines were Leu-7 positive while an adenocarcinoma and squamous cell carcinoma were negative. These results indicate that expression of Leu-7 antigen on lung tumor cells is heterogeneous both in vitro and in vivo. Small cell lung tumor lines have been reported to undergo histological conversion in vitro accompanied by the loss of a number of biochemical markers. In our study histologically converted cells exhibited much less reactivity with HNK-1 than did the parent cells. These results indicate that the degree of expression of Leu-7 antigen may be under the control of differentiation-related events. Thus monoclonal antibody HNK-1 has been very useful in studying heterogeneity within and among lung tumor cells.