Human transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are caused by the accumulation of an abnormal isoform of the prion protein in the CNS. Creutzfeldt-Jakob disease in its sporadic form is the most frequent type of human TSE. At present, there is no proven specific or effective treatment available for any form of TSE. Pentosan polysulfate (PPS) has been shown to prolong the incubation period when administered to the cerebral ventricles in a rodent TSE model. Cerebroventricular administration of PPS has been carried out in 26 patients with TSEs and has been shown to be well tolerated in doses < or = 220 microg/kg/day. Proof of efficacy has been difficult because the specific and objective criteria for measurement of response have not been established yet. Preliminary clinical experience confirms extended survival in patients with variant Creutzfeldt-Jakob disease receiving intraventricular PPS; however, it is still not clear if this is due to PPS itself. Further prospective investigations of long-term intraventricular PPS administration are essential for the assessment of its effects.