The HCT-8R clone of the HCT-8 human colon tumor line, which expresses increased quantities of carcinoembryonic antigen (CEA) on its surface, was discovered to have an enhanced susceptibility to lysis by natural killer (NK) cells in human peripheral blood. This increase in susceptibility to lysis by peripheral blood mononuclear cells was not explained by stimulation of interferon release by HCT-8R cells but rather was found to be attributable to an increased susceptibility of HCT-8R cells to lysis by those NK cells that bind to sheep erythrocytes (E-RFC). Cold target competition experiments and single-cell assay for cytotoxic cells suggested that the presence of surface CEA did not increase lysis of HCT-8R by facilitating "recognition" by E-RFC-type cytotoxic cells but by rendering HCT-8R cells more susceptible to the lytic mechanism of NK cells. The magnitude of expression of surface CEA by a variety of human carcinoma cell lines with a few exceptions and subclones of HCT-8 also correlated with increased susceptibility to lysis by blood mononuclear cells. The possible clinical significance of these findings was discussed.