As an incidental finding in a separate, ongoing investigation, dexamethasone was shown to sensitise mice fatally to a later challenge with a normally-tolerated dose of cycloheximide. This phenomenon is described here; it is also shown that two unrelated agents, namely promethazine and nordihydroguauaretic acid, duplicated this sensitising effect of the steroid. The three drugs have in common the ability to inhibit powerfully the synthesis of tumour necrosis factor-alpha in response to lipopolysaccharide, and it is suggested that this property is linked to their ability to induce fatal cycloheximide intolerance. Such drug-pretreated mice were protected if given dexamethasone at the time of cycloheximide challenge. An equal degree of protection was conferred on such animals by oral antibiotic treatment known to eliminate the aerobic intestinal flora. This indicated that the three agents induced fatal susceptibility to cycloheximide through the agency of the gut flora. It is proposed that the three drugs act by impairing the hepatic mechanism which normally removes portal vein-borne endogenous lipopolysaccharide, leading to systemic distribution of lipopolysaccharide, which is known from previous work, using a small dose of intraperitoneally injected lipopolysaccharide, to render mice fatally susceptible to a later cycloheximide challenge.