Cerebral malaria is a severe complication of infection with Plasmodium berghei ANKA involving the Th1 cytokines TNF-alpha and IFN-gamma. Suppressor of cytokine signalling-1 (SOCS1) is an important component in the regulatory cascade controlling inflammatory responses and signalling through IFN-gamma. Contrary to the expectation that SOCS1-deficient mice, in which IFN-gamma responses are uncontrolled and which are more sensitive to IFN-gamma, may show heightened susceptibility, mice lacking SOCS1 were protected from cerebral malaria. Unlike the controls and despite similar parasitaemia, infected SOCS1 null mice showed no inflammation or haemorrhaging in the brains. Mice lacking SOCS1 exhibited decreased splenic cellularity and a reduced ratio of CD4 : CD8 lymphocytes, which were maintained during infection. However, the ratio of IFN-gamma to IL-4 mRNA expression during infection was similar in SOCS1 -/- and control mice suggesting that a dramatic shift in the ratio of Th1 : Th2 responses does not account for the resistance to disease. Resistance conferred by the lack of SOCS1 is specific since the related SOCS2, also implicated in Th1-mediated responses, did not seem to be involved in the development of disease. Understanding the mechanism by which SOCS1 deficiency protects mice from cerebral malaria may allow the manipulation of its activity and alleviate pathology.