Cryptococcosis is a classical systemic opportunistic mycosis, primarily occurring among patients with significant immunologic impairment. However, this disease could also affect patients without any recognized immunologic defects, that is, phenotypically normal patients. The medical records of 29 non-HIV/nontransplant patients with cryptococcal disease during the period 2007-2014 were retrospectively reviewed. The most common site of infection was the central nervous system (n = 25, 86.2%), followed by the pulmonary system (n = 11, 37.9%) and blood (n = 2, 6.8%). Thoracic- and brain-computed tomography demonstrated abnormalities of 81.2% (n = 13) and 62.5% (n = 15), respectively. In sum, 22% (n = 6) of the patients experienced a significant underlying condition. More than one therapeutic regimen was used in 77.8% (n = 21) of the patients. The isolates were identified as being Cryptococcus neoformans species complex (n = 4, 36.4%) and Cryptococcus gattii species complex (n = 7, 63.6%). The overall mortality was 20.7% (n = 6). Herein, we presented the first case series of cryptococcosis in this specific population in São Paulo City, Brazil. The incidence of cryptococcosis in our hospital has not increased in recent years, and 77.8% (n = 21) of cases had no obvious predisposing factor. However, this disease remains associated with high mortality.