The varieties of Cryptococcus neoformans serotypes are neoformans and gattii. Data suggest an association between cryptococcal variety and host immune status. In addition, the two varieties differ in their epidemiology and pathogenicity. Furthermore, symptoms, outcome, and response of cryptococcosis to antifungal therapy may vary. The two varieties also differ in immune-modulating effects. Sparse clinical data suggest var. gattii is more virulent and may be more recalcitrant to antifungal therapy. Also, its infections produce more sequelae. A better understanding of how cryptococcal variety influences the clinical course and response to the treatment of cryptococcosis is needed. Clinicians should be aware of the association, especially in patients with refractory disease. It may be useful to type the isolate to the variety level and administer prolonged antifungal therapy.