Conscious, unrestrained cats given multiple injections of sodium arachidonate into a lateral cerebral ventricle responded with prolonged increases in both temperature. Development of tolerance was indicated by a gradual reduction in the response to successive doses. Cross-tolerance developed to hyperthermic actions of intraventricular bacterial endotoxin and prostaglandin E1 but not to leukocytic pyrogen given IV. Tolerance to the centrally administered agents was associated with enlargement of the cerebral ventricles and was therefore at least partially due to dilution of injected solutions by the increased volume of cerebrospinal fluid. The lateral ventricles were the most affected, particularly on the side of injection. There was no indication of physical obstruction within the ventricular system. Light microscopic examination revealed regions of chronic granulomatous inflammation of the subependymal zone of the periventricular tissues. The hydrocephalus was not secondary to the large number of intraventricular injections per se, to alkalinity of the arachidonate solution or to intermittent development of hyperthermia and was apparently a specific response to arachidonate. Intraventricular administration of arachidonate provides a means of inducing hydrocephalus with minimal morbidity and mortality.