The possible role of complement factor 5a (C5a) and prostaglandin E2 (pGE₂) in cerebrospinal fluid (CSF) pleocytosis and protein accumulation was assessed in a rabbit model of meningitis. Intracisternally administered C5a caused a rapid, early influx of leukocytes into CSF that peaked at 1 h after injection; by 6 h, cell counts were slightly higher than those in controls. Administration of PGE₂ or saline did not induce detectable CSF leukocytosis. Coadministration of PGE₂ with C5a decreased CSF leukocytosis in a dose-related fashion. Protein concentration increased 30 min after administration of C5a, peaked after 1 h, and remained elevated for 6 h. PGE₂ caused a dose-related increase in protein content after 2 h, whereas coadministration caused an inversely dose-related inhibition of the C5a-induced protein influx into CSF. These data sugest that PGE₂ in the subarachnoid space exerts an inhibitory action on the C5a-mediated response that is probably not related to its direct effects on protein extravasation.