Cryptococcus neoformans causes life-threatening meningoencephalitis. Human immunodeficiency virus (HIV) infection is the most significant predisposing condition, but persons with other immunodeficiency states as well as phenotypically normal persons develop cryptococcosis. We retrospectively reviewed medical records of all patients with a diagnosis of cryptococcosis between 2005 and 2017 at our inner-city medical center in the Bronx, an epicenter of AIDS in New York City, and analyzed demographic data, clinical manifestations, laboratory findings, treatment, and mortality for these patients. In sum, 63% of the cases over this 12-year period occurred in HIV-infected patients. And 61% of the HIV-infected patients were non-adherent with antiretroviral therapy, 10% were newly diagnosed with AIDS, and 4% had unmasking cryptococcus-associated immune reconstitution inflammatory syndrome. The majority were Hispanic or black in ethnicity/race. HIV-uninfected patients (47/126) were older (P < .0001), and the majority had an immunocompromising condition. They were less likely to have a headache (P = .0004) or fever (P = .03), had prolonged time to diagnosis (P = .04), higher cerebrospinal fluid (CSF) glucose levels (P = .001), less CSF culture positivity (P = .03), and a higher 30-day mortality (P = .03). Cases in HIV-uninfected patients were often unsuspected during their initial evaluation, leading to a delay in infectious diseases consultation, which was associated with mortality (P = .03). Our study indicates that HIV infection remains the most important predisposing factor for cryptococcosis despite availability of antiretroviral therapy and highlights potential missed opportunities for earlier diagnosis and differences in clinical and prognostic factors between HIV-infected and HIV-uninfected patients.