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Malaria is an important problem of public health. It is estimated that 350 to 500 million clinical cases occur annually, which cause 1.1 and 1.3 million deaths every year. The excessive activation of the immune system plays an important role in the pathogenesis of the disease. The cells of the immune system of Plasmodium-infected individuals not only produce large amounts of cytokines, which have anti-parasite effects, but also participate in the pathogenesis of the severe complications of malaria. A central feature of P. falciparum infection is the sequestration of parasitized erythrocytes within the small vessels of major organs. This involves molecular interactions between antigens of parasitized erythrocytes and host receptors, expressed on the surface of endothelial cells. The increased production of pro-inflammatory cytokines and nitric oxide, followed by the up regulation of endothelial cell adhesion molecules, influences the progression of cerebral lesions. The association of drugs capable of modulating the immune response to anti plasmodial drugs has been evaluated. Antibodies to tumor necrosis factor, pentoxifylline, and thalidomide have been tried for this purpose with variable success. This review submitted this subject to a critical assessment and suggests ways to take advantage of immunomodulatory drugs, associated to anti parasite therapy, to reduce the morbimortality of malaria.