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Cerebral malaria (CM) is an infrequent but serious complication of Plasmodium falciparum infection in humans. Animal and human studies suggest that the pathogenesis of CM is immune mediated, but the precise mechanisms leading to cerebral pathology are unclear. In mice, infection with Plasmodium berghei ANKA results in CM on day 6 postinoculation (p.i.), while infection with the closely related strain P. bergheiK173 does not result in CM. Infection with P. berghei K173 was associated with increased plasma gamma interferon (IFN-) at 24 h p.i. and with increased splenic and hepatic mRNAs for a range of cytokines (IFN-, interleukin-10 [IL-10], and IL-12) as well as the immunoregulatory enzyme indoleamine 2,3-dioxygenase. In contrast, P. berghei ANKA infection was associated with an absence of cytokine production at 24 h p.i. but a surge of IFN- production at 3 to 4 days p.i. When mice were coinfected with both ANKA and K173, they produced an early cytokine response, including a burst of IFN- at 24 h p.i., in a manner similar to animals infected with P. bergheiK173 alone. These coinfected mic