The present study shows that treatment with recombinant human tumour necrosis factor-α (rhTNF-α) can suppress parasitaemia and prevents development of experimental cerebral malaria (ECM) in Plasmodium berghei K173-infected mice. Mice received rhTNF-α treatment either by subcutaneous injection of free or liposome-encapsulated rhTNF-α or sustained intraperitoneal administration of rhTNF-α given via mini-osmotic pumps. Low-dose treatment with a subcutaneous bolus injection of rhTNF-α protected against ECM when treatment was started on day 5 or 6 after infection. The same protective efficacy was obtained either by subcutaneous injection of liposome-encapsulated rhTNF-α or by sustained release from osmotic pumps, but in the latter case a 10-fold lower daily dose of rhTNF-α was sufficient. Treatment with rhTNF-α substantially suppressed parasitaemia in ECM-protected mice, but not in mice developing ECM. Thus, the rhTNF-α mediated suppression of parasitaemia is directly or indirectly involved in protection against ECM. Sustained delivery of rhTNF-α through osmotic pumps, but not by subcutaneous injection of liposome-encapsulated rhTNF-α, resulted in increased concentrations of soluble mouse TNF receptor R75 (sTNFR75) in plasma at day 9 after infection when non-treated mice die of ECM. Thus, protection against ECM is not directly correlated with the sTNFR75 concentrations at day 9 after infection.