The pathogenesis of increased blood-brain barrier permeability during Cryptococcus meningitis is still largely unknown. Interleukin (IL-6) is a multifunctional cytokine, and numerous studies have shown that IL-6 influences the integrity of the blood-brain barrier. In this study we investigated the role of IL-6 in Cryptococcus meningitis. First, wild-type or IL-6-/- mice were injected with Cryptococcus neoformans (C. neoformans) and the survival time in both groups was recorded. Second, the number of fungi was measured in the brains of IL-6-/- wild-type mice. Finally, the blood-brain barrier permeability index was detected in infected IL-6-/- mice treated with recombinant human IL-6. The blood-brain barrier permeability index was measured in infected wild-type mice treated with anti-IL-6 antibodies as well. The survival of IL-6-/- mice injected with C. neoformans was significantly lower than that of identically challenged wild-type mice. The infected IL-6-/- mice had significantly larger brain fungal burdens than wild-type mice. Furthermore, increased blood-brain barrier index was found in infected IL-6-/- mice when compared with that in infected control mice. Similar results were obtained when mice challenged with C. neoformans were treated systemically with neutralizing anti-IL-6 antibodies, resulting in an elevation of vascular permeability. Our data revealed that IL-6 reduced the blood-brain barrier permeability during Cryptococcus meningitis, and it might provide an explanation for the significantly lower survival of infected IL-6-/- mice.