We have examined the effect of various cell monolayers on the ability of mouse spleen cells to lyse tumor cell targets (natural cytotoxicity reaction). Natural killer (NK) cell activity was reduced by as much as 75% depending on the cell substrate, with the greatest protection afforded by endothelial cells. Cell adhesion to the underlying cell monolayer was directly correlated with the degree of protection from lysis. Since it has previously been shown that tumor cells manifest selective adhesion to endothelial cells from those organs to which they are likely to metastasize, the experiments suggest a means by which natural surveillance mechanisms might be circumvented during the metastatic process.