The role of CD56 in the process of target cell killing by NK cells has been investigated. Addition of NK cells to HuH28 cells, a CD56-expressing cell line, led to inhibition of the growth of the target cells, which exhibited morphological features of apoptosis. These changes were prevented by the addition of a polyclonal anti-NCAM to the cultures. Since neither Fas antigen expression nor apoptotic changes were induced by addition to a mixed culture supernatant of NK and target cells, both the Fas-Fas ligand system and soluble factors do not seem to participate in apoptosis in these circumstances. Increased secretion of interferon-γ and tumour necrosis factor-α by NK cells must therefore have been suppressed by the presence of the polyclonal antibody. These results lead us to conclude that CD56, through homophilic binding, plays an important role in the process of target cell killing by an apoptosis mechanism.