Blastomycosis is thought to be endemic to specific regions of the United States. The spectrum of disease ranges from subclinical infections to potentially fatal systemic dissemination. Single organ involvement often involves the lungs. Extrapulmonary dissemination often includes the skin, bone, and genitourinary systems. There are rare reports of isolated central nervous system blastomycosis. Herein, we report a case of isolated central nervous system infection in a patient residing in New York State without travel to known endemic regions. Diagnosis was established as Blastomyces dermatitidis by morphologic characteristics of biopsied tissue and was confirmed through real-time polymerase chain reaction assays. In addition, the culture was confirmed as B. dermatitidis by conventional and real-time polymerase chain reaction assay. The patient was treated with prolonged antifungal therapy and is clinically well. This report suggests an expansion of the endemic geography of blastomycosis and highlights the utility of molecular methods for diagnosis.