The effect of RGD-sequence-containing pentapeptides and monoclonal antibodies (MAbs) against the adhesion molecules CDI la-dCD18, ICAM-I (CD54) and CD2 on the binding and cytotoxicity of endogenous (freshly purified) and IL-2 -I t' imulated CD3-negative N K cells has been studied. Antibody to CD18 exerted the most significant inhibition of adhesion and cytotoxicity of endogenous NK cells to MOLT-4 lymphoma cells, followed by antibodies to CD2 and CD54. Antibodies to either C D I I a, C D I I b or C D I Ic did not inhibit adhesion when used separately, whereas as a mixture their inhibitory capacity was as strong as that of anti-CDl8. Antibodies against CD18, CD54 and CD2 exerted an additive effect on the inhibition of adhesion. Their combination eradicated the binding of endogenous NK cells. The RGD-containing peptide did not inhibit the binding or cytotoxicity of freshly purified NK cells to MOLT-4, whereas some inhibition was detected against the adenocarcinoma cell line COLO-205. According to FACS analysis, IL-2 increases the expression of CD2 and CD54 on NK cells. However, the relative contribution of the adhesion molecules to the N K cell binding did not change as a result of the stimulation with IL-2. The RGD-peptide substantially inhibited the binding of 1L-2-stimulated killer cells to COLO, and the combination of this peptide with MAbs to CD18, CD54 and CD2 practically blocked the adhesion. Our results indicate that both C D I Ia-dCD18-(involving the 3 heterodirners) and CD2-dependent adhesion pathways are used by LGL in endogenous and IL-2 stimulated natural killing. In addition, RGD-binding receptors are involved in adhesion to some target cells.