Peripheral blood lymphocytes cultured with interleukin-2 (IL-2), which are referred to as lymphokine-activated killer (LAK) cells, develop the ability to lyse a wide variety of tumor cells but not normal cells. However, we report here that a cloned human natural killer cell line, NK3.3, was susceptible to lysis by human LAK cells. An IL-4-dependent NK3.3 subclone showed higher sensitivity to LAK-mediated lysis than the conditioned medium-dependent parent clone or the IL-2-dependent NK3.3 subclone. Cytokine-"starved" NK3.3 cells, which were cultured in medium lacking IL-2 or IL-4, exhibited a decreased susceptibility to LAK cell lysis. Periodate treatment of NK3.3 cells, which can induce nonspecific binding between effector cells and target cells through Schiff-base formation, enhanced the sensitivity to LAK, suggesting that adhesion molecules may be involved in this killing mechanism. The "starved" NK3.3 cells expressed lower levels of intracellular adhesion molecule 1 (ICAM-1); however, anti-ICAM-1 antibody could not inhibit the sensitivity of the NK3.3 clone to LAK lysis. These results suggest that ICAM-1 is not the major ligand in NK3.3 sensitivity, although the sensitivity correlates well with the magnitude of ICAM-1 expression.