Background: C-reactive protein (CRP) level correlates with parasitemia and severity of malaria, but whether this reflects causality remains unknown. Methods: Using CRP-transgenic and CRP-deficient mice we compared the onset and severity of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA). Results: CRP-deficient mice were most resistant to ECM. Conclusions: CRP might contribute to the development of cerebral malaria, rather than protect against it. © The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved.