It has been reported that treatment with homologous interferon of cells in culture interferes with the process of diphtheria intoxication in these cells. This report both confirms and extends this observation. The most sensitive indicator of diphtheria toxin action in cells, i.e., the inhibition of incorporation of labeled amino acids into protein, was employed, and human, mouse, and chicken interferon-cell systems were studied. Interferon treatment afforded a distinct, reproducible protection from the action of toxin, but in no case could total protection be shown. The "antitoxic" component is stable at pH 2, is species-specific, is not sedimented at 100,000 x g, and is trypsin-sensitive. Human cell preparations are heat-labile. Experiments with cell-free amino acid incorporation systems suggest that the "anti-toxic" effect of interferon is concentrated at the level of the cell membrane and subcellular components are not directly involved.