CNS infection occurs in 5 to 10% of patients with disseminated histoplasmosis. The recognition, diagnosis, and treatment of CNS histoplasmosis is not well–characterized. Over one third of cases reported, have occurred in immunocompetent individuals. Morbidity, and mortality appear to be high in patients with CNS histoplasmosis with high rates of relapse. Despite prolonged courses of treatment, the case fatality was 39% with half of the survivors relapsing in a prior study. Clinicians should have a low threshold for considering histoplasmosis as a cause for meningitis, brain lesions, vascular events, or hydrocephalus in immunocompromised, and non–immunocompromised patients who reside in endemic areas, and for whom an alternative diagnosis has not been established.