Prostaglandin D(2) (PGD(2)) is involved in a variety of physiological and pathophysiological processes, but its role in fever is poorly understood. Here we investigated the effects of central PGD(2) administration on body temperature and prostaglandin levels in the cerebrospinal fluid (CSF) of rats. Administration of PGD(2) into the cisterna magna (i.c.m) evoked a delayed fever response that was paralleled by increased levels of prostaglandin E(2) (PGE(2)) in the CSF. The elevated PGE(2) levels were not caused by an increased expression of cyclooxygenase 2 or microsomal prostaglandin E synthase-1 in the hypothalamus. Interestingly, i.c.m. pretreatment of animals with PGD(2) considerably sustained the pyrogenic effects of i.c.m. administered PGE(2). These data indicate that PGD(2) might control the availability of PGE(2) in the CSF and suggest that centrally produced PGD(2) may play a role in the maintenance of fever.