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Histoplasmosis is the most common endemic mycosis in the United States and is caused by the organism Histoplasma capsulatum. Infection is often asymptomatic or self-limited, but when symptomatic it usually presents in the form of pulmonary histoplasmosis. In its most severe form, H. capsulatum can spread to extrapulmonary sites causing disseminated infection. Here we present a peculiar case of central nervous system (CNS) histoplasmosis wherein multiple focal spinal cord lesions were the only manifestation of CNS infection, causing bilateral lower extremity paresis and loss of sensation. Although uncommon, CNS histoplasmosis should be included in the differential diagnosis when a patient presents with meningitis, encephalitis, or isolated brain or spinal cord lesions in endemic areas.