Wake RM, et al. - In the current study it was determined if the high mortality rates among asymptomatic cryptococcal antigen (CrAg)–positive patients identified through CrAg screening, despite pre-emptive fluconazole treatment, could be due to undiagnosed cryptococcal meningitis. In asymptomatic patients and patients with headaches only, the blood CrAg titers were significantly associated with concurrent cryptococcal meningitis. Concurrent cryptococcal meningitis was demonstrated in about one-third of asymptomatic CrAg-positive patients. More effective clinical assessment strategies and anti-fungal regimens are required for CrAg-positive patients, including investigation for cryptococcal meningitis irrespective of symptoms. Blood CrAg titers are recommended to target those most at risk of cryptococcal meningitis when it is not possible to perform lumbar punctures in CrAg-positive patients.