Interferon-treated cells exhibited an increased susceptibility to the toxicity of several natural and synthetic double-stranded RNA molecules and to vaccinia virus, provided the latter was able to undergo replicative events. However, interferon-treated cells exhibited no enhanced susceptibility to several other toxic materials or to vaccinia virus that was unable to replicate. These findings suggest that interferon-treated cells exhibit a specific enhanced susceptibility to the toxicity of double-stranded RNA molecules. Since neither RNA nor protein synthesis was required for toxicity to occur in interferon-treated cells exposed to polyriboinosinic-polyribocytidylic acid, it appears that the double-stranded RNA configuration is directly lytic for interferon-treated cells.