The contribution of the Toll-like receptor (TLR) cascade to the pathogenesis of cerebral malaria (CM) is controversially discussed. TLR2 and TLR9 were reported to be involved in the induction of CM in a study while recently TLR signaling was shown to be dispensable for the development of CM. Using Plasmodium berghei ANKA (PbA) infection of mice as a model of CM, we demonstrate here that the induction of CM is independent of TLR2, 4 and 9. Using triple TLR2/4/9-deficient mice, we exclude synergistic effects between the single TLRs that have been previously implicated with malaria pathology. In conclusion, this study shows that the activation of the innate immune response and the development of CM is not dependent on the engagement of TLR2/4/9.