Cladophialophora bantiana is associated with central nervous system infection and a poor outcome. C. bantiana tends to be resistant to amphotericin B. Accordingly, we evaluated amphotericin B and three triazoles--posaconazole, itraconazole, and fluconazole--for treatment of C. bantiana infection in mice. In immunosuppressed ICR mice infected intravenously, posaconazole, itraconazole, and amphotericin B prolonged survival. This improvement in survival corresponded with a reduction in brain fungal concentrations for mice which were given itraconazole and posaconazole, but not amphotericin B. In nonimmunosuppressed BALB/c mice infected intracerebrally, posaconazole showed dose-dependent responses in survival and reduction of brain tissue counts. These responses were observed for short, delayed, and prolonged therapy. Although posaconazole prolonged the survival of mice with reductions in brain fungal counts, it did not sterilize brain tissue with continuous therapy for 8 weeks. We concluded that posaconazole shows promise for the treatment of C. bantiana brain infections.