Abstract Background Cryptococcal meningitis (CM) is responsible for 15-20% of human immunodeficiency virus (HIV)-associated mortalities. CM prevalence has also increased in other immunocompromised populations of transplant recipients, cancer patients, and individuals on immunomodulatory medication. Methods This retrospective review included 51 definitive cases of CM hospitalized at a tertiary academic medical center in New York City between 2010 and 2023. We assessed clinical features and outcomes of CM, with additional analysis of factors related to antiretroviral therapy (ART)-adherence in HIV-infected cases and immunomodulatory medication history of HIV-negative cases. Results The cohort had a mean (SD) age of 47.1 ± 15.1 years, and was predominantly male (37, 72.5%). Of 32 HIV-infected patients, 3 (9.4%) were newly diagnosed with HIV at the time of CM hospitalization, 5 (15.6%) had recurrent CM, and 2 (6.3%) patients had a CM relapse. The majority (30, 93.8%) of HIV-infected patients were ART-non adherent. Of 19 HIV-negative patients, 8 (42.1%) were solid-organ transplant recipients, 5 (26.3%) had autoimmune conditions of sarcoidosis or systemic lupus erythematosus (SLE), and 3 (15.8%) had chronic lymphocytic leukemia (CLL). Six (11.8%) patients expired during hospitalization, 4 of whom were HIV-infected. Conclusion The burden of CM in people living with HIV (PLWH) and immunocompromised patients continues even in settings with accessible standard antifungal treatment though interventions of increased ART-adherence for HIV-infected individuals and antifungal prophylaxis may improve morbidity and mortality.