Nitric oxide (NO) is a short-lived biological mediator which can be induced in various cell types and is able to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of NO production by transcriptional upregulation of inducible nitric oxide synthase. In the present study, we used mice devoid of functional interferon regulatory factor 1 by targeted gene disruption (IRF-1^/) to investigate the role of NO in the host immune response against blood-stage Plasmodium berghei ANKA infection. IRF-1^/ mice survived longer with a later onset of and a lower peak parasitemia despite the inability to produce appreciable levels of NO. The administration of exogenous interleukin-12 (IL-12) was able to prolong survival in the wild-type mice with an upregulation in the expression of both gamma interferon (IFN-) and NO. However, the administration of IL-12 did not improve the survival of IRF-1^/ mice. These studies indicate that while IL-12 is able to mediate protection via an IFN-- and NO-dependent pathway in the wild-type mice, such a protective mechanism may not be functional in the IRF-1^/ mice. Our results suggest that NO may not be essential for host immunity to the parasite and that IRF-1^/ mice are able to induce an IFN-- and NO-independent mechanism against P. berghei infection.