Background. Central nervous system (CNS) involvement with Blastomyces dermatitidis is an uncommon and potentially fatal complication of blastomycosis. Methods. We retrospectively reviewed 22 patients with CNS blastomycosis at our institutions from 1990 through 2008 (13 proven, 5 probable, and 4 possible cases). Results. Magnetic resonance imaging was used in most patients, alone or in addition to computed tomography. CNS blastomycosis manifested as epidural abscess (1 of 22), meningitis (7 of 22), intracranial mass lesions (10 of 22), and concomitant intracranial mass lesions and meningitis (4 of 22). All patients received amphotericin B deoxycholate or a lipid formulation of amphotericin B as part of their treatment regimens. Most patients received amphotericin B followed by a prolonged course of oral azole therapy (voriconazole, fluconazole, or itraconazole). Four (18%) of 22 patients died during follow-up. Conclusions. On the basis of these data, we recommend initial treatment with a lipid formulation of amphotericin B followed by a prolonged course of oral azole therapy, preferably voriconazole. © 2010 by the Infectious Diseases Society of America. All rights reserved.