Human central nervous system (CNS) aspergillosis has >90% mortality. We compared posaconazole with other antifungals for efficacy against murine CNS aspergillosis. All tested regimens of posaconazole were equivalent to those of amphotericin B and superior in prolonging survival and reducing CFU to those of itraconazole and caspofungin and to vehicle controls. No antifungal regimen effected cure. No toxicity was noted. Overall, posaconazole shows potential for treating CNS aspergillosis.