A 3-year-old female German Shepherd Dog was evaluated for progressive mental obtundation and vestibular signs. Central nervous system cryptococcosis was diagnosed on the basis of growth of Cryptococcus neoformans in fungal culture of CSF, as well as detection of the organism in CSF via microscopy. Cryptococcal capsular latex antigen agglutination titer was 1:262,144 in CSF and 1:1,048,576 in serum samples. Imaging with magnetic resonance augmented diagnosis. The dog improved after long-term treatment with fluconazole. Fluconazole is useful in the treatment of CNS cryptococcosis, because it attains high concentration in the CNS. Long-term therapy is often required for resolution of clinical signs, and affected animals may require long-term follow-up with periodic evaluation of CSF via fungal culture and latex agglutination tests. Monitoring serum latex agglutination test results may provide a safe, less invasive means of monitoring response to treatment.