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Cerebral malaria is a severe complication of Plasmodium falciparum infection. Although T-cell activation and type II IFN-γ are required for Plasmodium berghei ANKA ( Pb A)-induced murine experimental cerebral malaria ( ECM), the role of type I IFN-α/β in ECM development remains unclear. Here, we address the role of the IFN-α/β pathway in ECM devel-opment in response to hepatic or blood-stage Pb A infection, using mice deficient for types I or II IFN receptors. While IFN-γ R1−/− mice were fully resistant, IFNAR1−/− mice showed delayed and partial protection to ECM after Pb A infection. ECM resistance in IFN-γ R1−/− mice correlated with unaltered cerebral microcirculation and absence of ischemia, while WT and IFNAR1−/− mice developed distinct microvascular pathologies. ECM resistance appeared to be independent of parasitemia. Instead, key mediators of ECM were attenuated in the absence of IFNAR1, including Pb A-induced brain sequestration of CXCR3+-activated CD8+ T cells. This was associated with reduced expression of Granzyme B, IFN-γ, IL-12 Rβ2, and T-cell-attracting chemokines CXCL9 and CXCL10 in IFNAR1−/− mice, more so in the absence of IFN-γ R1. Therefore, the type I IFN-α/β receptor pathway contributes to brain T-cell responses and microvascular pathology, although it is not as essential as IFN-γ for the development of cerebral malaria upon hepatic or blood-stage Pb A infection. [ABSTRACT FROM AUTHOR]