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Background: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete., Methods: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included., Results: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89)., Conclusions: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV., Competing Interests: Potential conflicts of interest . T. S. has received consulting fees for serving on advisory boards and steering committees from Biogen. O. M. has received grants from Gilead Sciences and Merck, Sharp and Dohme Australia and honoraria from Gilead Sciences; support for attending meetings from F2G; and participated on data and safety monitoring boards (DSMB) or advisory boards for Gilead Sciences and Merck, Sharp and Dohme Australia. K. J. K. has received payment for expert testimony at the 46th Society of Hospital Pharmacists of Australia National Conference. A. R. T. has received honoraria from the Medical Journal of Australia, paid to institution, and reports grants or contracts from CTRA with the University of Melbourne (reimbursement of costs paid to institution). B. W. T. is supported by a Medical Research Future Fund Investigator Fellowship; has received grants from MSD and Seqirus; has received honoraria from Pfizer, Alexion, and Janssen; and participated on DSMBs or advisory boards for CSL­Behring, Takeda, and Moderna. S. C. A. C. has received educational grants from F2G and MSD Australia; reports untied educational grants from MSD Australia and F2G Pty Ltd; and reports a role as editor-in-chief for Medical Mycology (journal of ISHAM). M. A. S. has received grants from Gilead Sciences, Merck, and F2G; has received honoraria from F2G; and participated on DSMBs or advisory boards for Pfizer, Cidara, and Roche. R. J. L. reports paid participation on a GSK advisory board. S. A. L. reports grants or contracts as principal investigator on 3 projects funded through a Hot North fund grant and a UK Government Fleming Fund Grant (as part of broader funding for the Menzies School of Health Research; no salary, project costs remunerated only); unpaid participation on a DSMB or advisory board for the Australian Academy of Science and the Australian Academy of Health and Medical Sciences roundtable of experts for the House of Representatives Committee on Health and Ageing; and an unpaid role as a National Tuberculosis Advisory Committee member. M. T. B. reports an unpaid role as an Advanced Training Committee member for General Medicine for the Royal Australasian College of Physicians and an unpaid member of the Vocational Training Committee for Medical Registrars in the Auckland region for the Northern Region Alliance. C. L. K. reports an unpaid role on the Australian Society of Infectious Diseases Board of Directors. E. W. reports a role as a committee member of the Australasian Society for Infectious Diseases Equity and Diversity Committee (unpaid). K. C. G. reports a role as a member of the New Zealand Committee of the Australasian Society for Infectious Diseases. All other authors report no potential conflicts. All authors have submitted the International Committee of Medical Journal Editors Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)