The effect of RGD‐sequence‐containing pentapeptides and monoclonal antibodies (MAbs) against the adhesion molecules CD) la‐c/CDIB, ICAM‐1 (CD54) and CD2 on the binding and cytotoxicity of endogenous (freshly purified) and IL‐2‐stimulated CD3‐negative NK cells has been studied. Antibody to CD 18 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 CD 11 a, CD 11 b or CD 11c did not inhibit adhesion when used separately, whereas as a mixture their inhibitory capacity was as strong as that of anti‐CD 18. Antibodies against CD 18, 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 NK cell binding did not change as a result of the stimulation with IL‐2. The RGD‐peptide substantially in hibited the binding of IL‐2‐stimulated killer cells to COLO, and the combination of this peptide with MAbs to CD 18, CD54 and CD2 practically blocked the adhesion. Our results indicate that both CD 11a‐c/CD18‐ (involving the 3 heterodimers) 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.