A 52-year-old male on chronic prednisone for polymyalgia rheumatica presented with a subacute history of headaches, nausea, phonophobia, intermittent diplopia and gait instability. He was hospitalized 2 weeks prior to presentation with extensive evaluations only notable for leptomeningeal inflammation on MRI. His symptoms progressively worsened and he developed aphasia. He was transferred to our facility where extensive spinal fluid examinations were repeated and were again nondiagnostic. Ultimately, a diagnostic skull-based biopsy was performed which demonstrated Blastomyces dermatitidis fungal meningitis. Despite extensive sampling and cultures, only 1 of the intraoperative samples yielded diagnostic results. This underscores the low sensitivity of current methods to diagnose CNS blastomycosis. This case suggests that a neurosurgical biopsy may be necessary and should be considered early in the diagnostic process, especially if a definitive diagnosis is elusive. If a biopsy is performed, sampling should be ample and from multiple areas. Following the diagnosis, our patient was treated with liposomal amphotericin B and then voriconazole with a good clinical response.