The killing of GL26 and YAC-1 cells by natural killer cells (NKC) is reduced in the presence of a monolayer of endothelial cells. This reduction in cytotoxicity correlates with the degree of adhesion between the tumor cells and the endothelial monolayers. The cytotoxicity of NKC toward glioma was 10% when carried out on plastic, but a monolayer of endothelium derived from brain inhibited the cytotoxicity by about 90%. Endothelium from thoracic duct and lung also inhibited cytotoxicity by about 90%, endothelium from aorta inhibited by 55% and that from ovary by only 45%. Cytotoxicity of NKC toward YAC-1 (a control NK target) was 40% on plastic, but a monolayer of endothelium from thoracic duct inhibited the cytotoxicity by 75%. Endothelium from brain and lung inhibited cytotoxicity by about 60%, aorta by 50%, and ovary by 40%. Interactions between tumor cells and the host-organ microvascular endothelium appear to protect neoplastic cells from natural surveillance mechanisms and may play a role in the formation of metastatic tumor deposits.