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In unanaesthetized cats the effect of lipid A on rectal temperature and on prostaglandin E2 (PGE2) activity in cisternal cerebrospinal fluid (c.s.f.) was examined. Lipid A was injected either intravenously or into the cerebral ventricles. 2. Lipid A injected intravenously in a dose of 1--4 mug/kg produced longlasting fever which was more often biphasic than monophasic. With a second injection a much shorter but usually hither monophasic response was produced. The cat was then for a time insensitive to I.V. lipid A but when the injections were repeated at 24 hr intervals brisk monophasic fevers were again produced. The threshold dose of I.V. lipid A lay between 0-1 and 0-3 mug/kg. 3. Lipid A injected into the cerebral ventricles in a dose of 100 ng or 1 mug produced long-lasting monophasic fever. No tolerance developed; the same or only slightly diminished responses occurred on repeated injections. The threshold dose was between 5 and 20 ng. 4. A cat rendered insensitive to I.V. lipid A gave its normal fever response to injection of lipid A into the cerebral ventricles. 5. The fever produced by lipid A injected I.V. or into the cerebral ventricles was associated with the appearance of, or a rise in PGE2 activity in c.s.f. 6. Both the fever and the PGE2 activity in c.s.f. produced by lipid A injected intravenously or into the cerebral ventricles were brought down and prevented by I.P. injections of aspirin, paracetamol, or indomethacin.