Cerebral phaeohyphomycosis caused by Ramichloridium mackenziei is universally fatal. All reported cases with long-term follow-up have indicated 100% mortality despite antifungal therapy and surgical intervention. We describe the case of a 62-year-old patient who underwent renal transplantation and had a cerebral abscess caused by R. mackenziei. The infection progressed despite surgical evacuation and therapy with liposomal amphotericin B, itraconazole, and 5-flucytosine. The patient was subsequently treated with the investigational triazole posaconazole oral suspension, 800 mg/day, in divided doses. Treatment with posaconazole resulted in progressive clinical and radiologic improvement. The patient is alive four years after diagnosis and maintained on posaconazole therapy. This case supports the potential role of this extended-spectrum azole in the treatment of this serious fungal infection of the central nervous system.